@article {1793221,
	title = {Regulatory T cells in dominant immunologic tolerance},
	journal = {J Allergy Clin Immunol},
	volume = {153},
	number = {1},
	year = {2024},
	month = {2024 Jan},
	pages = {28-41},
	abstract = {Regulatory T cells expressing the transcription factor forkhead box protein 3 mediate peripheral immune tolerance both to self-antigens and to the commensal flora. Their defective function due to inborn errors of immunity or acquired insults is associated with a broad range of autoimmune and immune dysregulatory diseases. Although their function in suppressing autoimmunity and enforcing commensalism is established, a broader role for regulatory T cells in tissue repair and metabolic regulation has emerged, enabled by unique programs of tissue adaptability and specialization. In this review, we focus on the myriad roles played by regulatory T cells in immunologic tolerance and host homeostasis and the potential to harness these cells in novel therapeutic approaches to human diseases.},
	keywords = {Autoimmune Diseases, Autoimmunity, Forkhead Transcription Factors, Humans, Immune System Diseases, Immune Tolerance, T-Lymphocytes, Regulatory},
	issn = {1097-6825},
	doi = {10.1016/j.jaci.2023.09.025},
	author = {Georgiev, Peter and Benamar, Mehdi and Han, SeongJun and Haigis, Marcia C and Sharpe, Arlene H and Chatila, Talal A}
}
@article {1793206,
	title = {Regulatory T cells in skin mediate immune privilege of the hair follicle stem cell niche},
	journal = {Sci Immunol},
	volume = {9},
	number = {91},
	year = {2024},
	month = {2024 Jan 05},
	pages = {eadh0152},
	abstract = {Immune tolerance is maintained in lymphoid organs (LOs). Despite the presence of complex immune cell networks in non-LOs, it is unknown whether self-tolerance is maintained in these tissues. We developed a technique to restrict genetic recombination to regulatory T cells (Tregs) only in skin. Selective depletion of skin Tregs resulted in T cell-mediated inflammation of hair follicles (HFs). Suppression did not rely on CTLA-4, but instead on high-affinity interleukin-2 (IL-2) receptor expression by skin Tregs, functioning exclusively in a cell-extrinsic manner. In a novel model of HF stem cell (HFSC)-driven autoimmunity, we reveal that skin Tregs immunologically protect the HFSC niche. Finally, we used spatial transcriptomics to identify aberrant IL-2 signaling at stromal-HF interfaces in a rare form of human alopecia characterized by HFSC destruction and alopecia areata. Collectively, these results reveal the fundamental biology of Tregs in skin uncoupled from the systemic pool and elucidate a mechanism of self-tolerance.},
	keywords = {Hair Follicle, Humans, Immune Privilege, Interleukin-2, Stem Cell Niche, T-Lymphocytes, Regulatory},
	issn = {2470-9468},
	doi = {10.1126/sciimmunol.adh0152},
	author = {Cohen, Jarish N and Gouirand, Victoire and Macon, Courtney E and Lowe, Margaret M and Boothby, Ian C and Moreau, Joshua M and Gratz, Iris K and Stoecklinger, Angelika and Weaver, Casey T and Sharpe, Arlene H and Ricardo-Gonzalez, Roberto R and Rosenblum, Michael D}
}
@article {1793216,
	title = {X-CHIME enables combinatorial, inducible, lineage-specific and sequential knockout of genes in the immune system},
	journal = {Nat Immunol},
	volume = {25},
	number = {1},
	year = {2024},
	month = {2024 Jan},
	pages = {178-188},
	abstract = {Annotation of immunologic gene function in vivo typically requires the generation of knockout mice, which is time consuming and low throughput. We previously developed CHimeric IMmune Editing (CHIME), a CRISPR-Cas9 bone marrow delivery system for constitutive, ubiquitous deletion of single genes. Here we describe X-CHIME, four new CHIME-based systems for modular and rapid interrogation of gene function combinatorially (C-CHIME), inducibly (I-CHIME), lineage-specifically (L-CHIME) or sequentially (S-CHIME). We use C-CHIME and S-CHIME to assess the consequences of combined deletion of Ptpn1 and Ptpn2, an embryonic lethal gene pair, in adult mice. We find that constitutive deletion of both PTPN1 and PTPN2 leads to bone marrow hypoplasia and lethality, while inducible deletion after immune development leads to enteritis and lethality. These findings demonstrate that X-CHIME can be used for rapid mechanistic evaluation of genes in distinct in vivo contexts and that PTPN1 and PTPN2 have some functional redundancy important for viability in adult mice.},
	keywords = {Animals, CRISPR-Cas Systems, Gene Editing, Immune System, Mice, Mice, Knockout, Protein Tyrosine Phosphatase, Non-Receptor Type 2},
	issn = {1529-2916},
	doi = {10.1038/s41590-023-01689-6},
	author = {LaFleur, Martin W and Lemmen, Ashlyn M and Streeter, Ivy S L and Nguyen, Thao H and Milling, Lauren E and Derosia, Nicole M and Hoffman, Zachary M and Gillis, Jacob E and Tjokrosurjo, Qin and Markson, Samuel C and Huang, Amy Y and Anekal, Praju V and Llopis, Paula Montero and Haining, W Nicholas and Doench, John G and Sharpe, Arlene H}
}
@article {1793281,
	title = {Age-associated remodeling of T~cell immunity and metabolism},
	journal = {Cell Metab},
	volume = {35},
	number = {1},
	year = {2023},
	month = {2023 Jan 03},
	pages = {36-55},
	abstract = {Aging results in remodeling of T~cell immunity and is associated with poor clinical outcomes in age-related diseases such as cancer. Among the hallmarks of aging, changes in host and cellular metabolism critically affect the development, maintenance, and function of T~cells. Although metabolic perturbations impact anti-tumor T~cell responses, the link between age-associated metabolic dysfunction and anti-tumor immunity remains unclear. In this review, we summarize recent advances in our understanding of aged T~cell metabolism, with a focus on the bioenergetic and immunologic features of T~cell subsets unique to the aging process. We also survey insights into mechanisms of metabolic T~cell dysfunction in aging and discuss the impacts of aging on the efficacy of cancer immunotherapy. As the average life expectancy continues to increase, understanding the interplay between age-related metabolic reprogramming and maladaptive T~cell immunity will be instrumental for the development of therapeutic strategies for older patients.},
	keywords = {Aged, Energy Metabolism, Humans, Immunotherapy, Neoplasms, T-Lymphocyte Subsets, Tumor Microenvironment},
	issn = {1932-7420},
	doi = {10.1016/j.cmet.2022.11.005},
	author = {Han, SeongJun and Georgiev, Peter and Ringel, Alison E and Sharpe, Arlene H and Haigis, Marcia C}
}
@article {1793201,
	title = {Antigen presentation deficiency, mesenchymal differentiation, and resistance to immunotherapy in the murine syngeneic CT2A tumor model},
	journal = {Front Immunol},
	volume = {14},
	year = {2023},
	month = {2023},
	pages = {1297932},
	abstract = {BACKGROUND: The GL261 and CT2A syngeneic tumor lines are frequently used as immunocompetent orthotopic mouse models of human glioblastoma (huGBM) but demonstrate distinct differences in their responses to immunotherapy.

METHODS: To decipher the cell-intrinsic mechanisms that drive immunotherapy resistance in CT2A-luc and to define the aspects of human cancer biology that these lines can best model, we systematically compared their characteristics using whole exome and transcriptome sequencing, and protein analysis through immunohistochemistry, Western blot, flow cytometry, immunopeptidomics, and phosphopeptidomics.

RESULTS: The transcriptional profiles of GL261-luc2 and CT2A-luc tumors resembled those of some huGBMs, despite neither line sharing the essential genetic or histologic features of huGBM. Both models exhibited striking hypermutation, with clonal hotspot mutations in RAS genes (Kras p.G12C in GL261-luc2 and Nras p.Q61L in CT2A-luc). CT2A-luc distinctly displayed mesenchymal differentiation, upregulated angiogenesis, and multiple defects in antigen presentation machinery (e.g. Tap1 p.Y488C and Psmb8 p.A275P mutations) and interferon response pathways (e.g. copy number losses of loci including IFN genes and reduced phosphorylation of JAK/STAT pathway members). The defect in MHC class I expression could be overcome in CT2A-luc by interferon-γ treatment, which may underlie the modest efficacy of some immunotherapy combinations. Additionally, CT2A-luc demonstrated substantial baseline secretion of the CCL-2, CCL-5, and CCL-22 chemokines, which play important roles as myeloid chemoattractants.

CONCLUSION: Although the clinical contexts that can be modeled by GL261 and CT2A for huGBM are limited, CT2A may be an informative model of immunotherapy resistance due to its deficits in antigen presentation machinery and interferon response pathways.},
	keywords = {Animals, Antigen Presentation, Glioblastoma, Humans, Immunotherapy, Interferon-gamma, Janus Kinases, Mice, Signal Transduction, STAT Transcription Factors},
	issn = {1664-3224},
	doi = {10.3389/fimmu.2023.1297932},
	author = {Iorgulescu, J Bryan and Ruthen, Neil and Ahn, Ryuhjin and Panagioti, Eleni and Gokhale, Prafulla C and Neagu, Martha and Speranza, Maria C and Eschle, Benjamin K and Soroko, Kara M and Piranlioglu, Raziye and Datta, Meenal and Krishnan, Shanmugarajan and Yates, Kathleen B and Baker, Gregory J and Jain, Rakesh K and Suv{\`a}, Mario L and Neuberg, Donna and White, Forest M and Chiocca, E Antonio and Freeman, Gordon J and Sharpe, Arlene H and Wu, Catherine J and Reardon, David A}
}
@article {1793246,
	title = {B-cell-specific checkpoint molecules that regulate anti-tumour immunity},
	journal = {Nature},
	volume = {619},
	number = {7969},
	year = {2023},
	month = {2023 Jul},
	pages = {348-356},
	abstract = {The role of B cells in anti-tumour immunity is still debated and, accordingly, immunotherapies have focused on targeting T and natural killer cells to inhibit tumour growth1,2. Here, using high-throughput flow cytometry as well as bulk and single-cell RNA-sequencing and B-cell-receptor-sequencing analysis of B cells temporally during B16F10 melanoma growth, we identified a subset of B cells that expands specifically in the draining lymph node over time in tumour-bearing mice. The expanding B cell subset expresses the cell surface molecule T cell immunoglobulin and mucin domain 1 (TIM-1, encoded by Havcr1) and a unique transcriptional signature, including multiple co-inhibitory molecules such as PD-1, TIM-3, TIGIT and LAG-3. Although conditional deletion of these co-inhibitory molecules on B cells had little or no effect on tumour burden, selective deletion of Havcr1 in B cells both substantially inhibited tumour growth and enhanced effector T cell responses. Loss of TIM-1 enhanced the type 1 interferon response in B cells, which augmented B cell activation and increased antigen presentation and co-stimulation, resulting in increased expansion of tumour-specific effector T cells. Our results demonstrate that manipulation of TIM-1-expressing B cells enables engagement of the second arm of adaptive immunity to promote anti-tumour immunity and inhibit tumour growth.},
	keywords = {Animals, Antigen Presentation, B-Lymphocytes, Flow Cytometry, Interferon Type I, Lymph Nodes, Lymphocyte Activation, Melanoma, Melanoma, Experimental, Mice, Receptors, Antigen, B-Cell, Single-Cell Gene Expression Analysis, T-Lymphocytes, Tumor Burden},
	issn = {1476-4687},
	doi = {10.1038/s41586-023-06231-0},
	author = {Bod, Lloyd and Kye, Yoon-Chul and Shi, Jingwen and Triglia, Elena Torlai and Schnell, Alexandra and Fessler, Johannes and Ostrowski, Stephen M and Von-Franque, Max Y and Kuchroo, Juhi R and Barilla, Rocky M and Zaghouani, Sarah and Christian, Elena and Delorey, Toni Marie and Mohib, Kanishka and Xiao, Sheng and Slingerland, Nadine and Giuliano, Christopher J and Ashenberg, Orr and Li, Zhaorong and Rothstein, David M and Fisher, David E and Rozenblatt-Rosen, Orit and Sharpe, Arlene H and Quintana, Francisco J and Apetoh, Lionel and Regev, Aviv and Kuchroo, Vijay K}
}
@article {1793226,
	title = {Formate Supplementation Enhances Antitumor CD8+ T-cell Fitness and Efficacy of PD-1 Blockade},
	journal = {Cancer Discov},
	volume = {13},
	number = {12},
	year = {2023},
	month = {2023 Dec 12},
	pages = {2566-2583},
	abstract = {UNLABELLED: The tumor microenvironment (TME) restricts antitumor CD8+ T-cell function and immunotherapy responses. Cancer cells compromise the metabolic fitness of CD8+ T cells within the TME, but the mechanisms are largely unknown. Here we demonstrate that one-carbon (1C) metabolism is enhanced in T cells in an antigen-specific manner. Therapeutic supplementation of 1C metabolism using formate enhances CD8+ T-cell fitness and antitumor efficacy of PD-1 blockade in B16-OVA tumors. Formate supplementation drives transcriptional alterations in CD8+ T-cell metabolism and increases gene signatures for cellular proliferation and activation. Combined formate and anti-PD-1 therapy increases tumor-infiltrating CD8+ T cells, which are essential for enhanced tumor control. Our data demonstrate that formate provides metabolic support to CD8+ T cells reinvigorated by anti-PD-1 to overcome a metabolic vulnerability in 1C metabolism in the TME to further improve T-cell function.

SIGNIFICANCE: This study identifies that deficiencies in 1C metabolism limit the efficacy of PD-1 blockade in B16-OVA tumors. Supplementing 1C metabolism with formate during anti-PD-1 therapy enhances CD8+ T-cell fitness in the TME and CD8+ T-cell-mediated tumor clearance. These findings demonstrate that formate supplementation can enhance exhausted CD8+ T-cell function. See related commentary by Lin et al., p. 2507. This article is featured in Selected Articles from This Issue, p. 2489.},
	keywords = {CD8-Positive T-Lymphocytes, Dietary Supplements, Formates, Humans, Neoplasms, Programmed Cell Death 1 Receptor, Tumor Microenvironment},
	issn = {2159-8290},
	doi = {10.1158/2159-8290.CD-22-1301},
	author = {Rowe, Jared H and Elia, Ilaria and Shahid, Osmaan and Gaudiano, Emily F and Sifnugel, Natalia E and Johnson, Sheila and Reynolds, Amy G and Fung, Megan E and Joshi, Shakchhi and LaFleur, Martin W and Park, Joon Seok and Pauken, Kristen E and Rabinowitz, Joshua D and Freeman, Gordon J and Haigis, Marcia C and Sharpe, Arlene H}
}
@article {1793306,
	title = {Human PD-1 agonist treatment alleviates neutrophilic asthma by reprogramming T cells},
	journal = {J Allergy Clin Immunol},
	volume = {151},
	number = {2},
	year = {2023},
	month = {2023 Feb},
	pages = {526-538.e8},
	abstract = {BACKGROUND: Neutrophilic asthma is associated with disease severity and corticosteroid insensitivity. Novel therapies are required to manage this life-threatening asthma phenotype. Programmed cell death protein-1 (PD-1) is a key homeostatic modulator of the immune response for T-cell effector functions.

OBJECTIVE: We sought to investigate the role of PD-1 in the regulation of acute neutrophilic inflammation in a murine model of airway hyperreactivity (AHR).

METHODS: House dust mite was used to induce and compare neutrophilic AHR in wild-type and PD-1 knockout mice. Then, the therapeutic potential of a human PD-1 agonist was tested in a humanized mouse model in which the PD-1 extracellular domain is entirely humanized. Single-cell RNA sequencing and flow cytometry were mainly used to investigate molecular and cellular mechanisms.

RESULTS: PD-1 was highly induced on pulmonary T cells in our inflammatory model. PD-1 deficiency was associated with an increased neutrophilic AHR and high recruitment of inflammatory cells to the lungs. Consistently, PD-1 agonist treatment dampened AHR, decreased neutrophil recruitment, and modulated cytokine production in a humanized PD-1 mouse model. Mechanistically, we demonstrated at the transcriptional and protein levels that the inhibitory effect of PD-1 agonist is associated with the reprogramming of pulmonary effector T cells that showed decreased number and activation.

CONCLUSIONS: PD-1 agonist treatment is efficient in dampening neutrophilic AHR and lung inflammation in a preclinical humanized mouse model.},
	keywords = {Animals, Asthma, Disease Models, Animal, Humans, Lung, Mice, Programmed Cell Death 1 Receptor, Th2 Cells},
	issn = {1097-6825},
	doi = {10.1016/j.jaci.2022.07.022},
	author = {Helou, Doumet Georges and Quach, Christine and Fung, Marshall and Painter, Jacob D and Hurrell, Benjamin P and Eddie Loh, Yong-Hwee and Howard, Emily and Shafiei-Jahani, Pedram and Soroosh, Pejman and Sharpe, Arlene H and Akbari, Omid}
}
@article {1793271,
	title = {Immune checkpoint receptors in autoimmunity},
	journal = {Curr Opin Immunol},
	volume = {80},
	year = {2023},
	month = {2023 Feb},
	pages = {102283},
	abstract = {Immune checkpoint receptors such as programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), and T cell immunoglobulin and ITIM domain (TIGIT) have distinct and overlapping inhibitory functions that regulate Tcell activation, differentiation, and function. These inhibitory receptors also mediate tolerance, and dysregulation of these receptors can result in a breach of tolerance and the development of autoimmune syndromes. Similarly, antibody blockade of immune checkpoint receptors or their ligands for cancer immunotherapy may trigger a spectrum of organ inflammation that resembles autoimmunity, termed immune-related adverse events (irAE). In this review, we discuss recent advances in the regulation of autoimmunity by immune checkpoint receptors. We highlight coordinated gene expression programs linking checkpoint receptors, heterogeneity within autoreactive T-cell populations, parallels between irAE and autoimmunity, and bidirectional functional interactions between immune checkpoint receptors and their ligands.},
	keywords = {Autoimmunity, CTLA-4 Antigen, Humans, Immune System Diseases, Immunotherapy, Ligands, Neoplasms, Receptors, Immunologic, T-Lymphocytes},
	issn = {1879-0372},
	doi = {10.1016/j.coi.2023.102283},
	author = {Burke, Kelly P and Patterson, Dillon G and Liang, Dan and Sharpe, Arlene H}
}
@article {1793266,
	title = {Losartan controls immune checkpoint blocker-induced edema and improves survival in glioblastoma mouse models},
	journal = {Proc Natl Acad Sci U S A},
	volume = {120},
	number = {6},
	year = {2023},
	month = {2023 Feb 07},
	pages = {e2219199120},
	abstract = {Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma trials. Here, we found that ICBs induce cerebral edema in some patients and mice with glioblastoma. Through single-cell RNA sequencing, intravital imaging, and CD8+ T cell blocking studies in mice, we demonstrated that this edema results from an inflammatory response following antiprogrammed death 1 (PD1) antibody treatment that disrupts the blood-tumor barrier. Used in lieu of immunosuppressive corticosteroids, the angiotensin receptor blocker losartan prevented this ICB-induced edema and reprogrammed the tumor microenvironment, curing 20\% of mice which increased to 40\% in combination with standard of care treatment. Using a bihemispheric tumor model, we identified a "hot" tumor immune signature prior to losartan+anti-PD1 therapy that predicted long-term survival. Our findings provide the rationale and associated biomarkers to test losartan with ICBs in glioblastoma patients.},
	keywords = {Animals, CD8-Positive T-Lymphocytes, Edema, Glioblastoma, Immune Checkpoint Inhibitors, Losartan, Mice, Tumor Microenvironment},
	issn = {1091-6490},
	doi = {10.1073/pnas.2219199120},
	author = {Datta, Meenal and Chatterjee, Sampurna and Perez, Elizabeth M and Gritsch, Simon and Roberge, Sylvie and Duquette, Mark and Chen, Ivy X and Naxerova, Kamila and Kumar, Ashwin S and Ghosh, Mitrajit and Emblem, Kyrre E and Ng, Mei R and Ho, William W and Kumar, Pragya and Krishnan, Shanmugarajan and Dong, Xinyue and Speranza, Maria C and Neagu, Martha R and Iorgulescu, J Bryan and Huang, Raymond Y and Youssef, Gilbert and Reardon, David A and Sharpe, Arlene H and Freeman, Gordon J and Suv{\`a}, Mario L and Xu, Lei and Jain, Rakesh K}
}
@article {1793231,
	title = {Metabolic modulation of mitochondrial mass during CD4 T~cell activation},
	journal = {Cell Chem Biol},
	volume = {30},
	number = {9},
	year = {2023},
	month = {2023 Sep 21},
	pages = {1064-1075.e8},
	abstract = {Mitochondrial biogenesis initiates within hours of T~cell receptor (TCR) engagement and is critical for T~cell activation, function, and survival; yet, how metabolic programs support mitochondrial biogenesis during TCR signaling is not fully understood. Here, we performed a multiplexed metabolic chemical screen in CD4+ T lymphocytes to identify modulators of metabolism that impact mitochondrial mass during early T~cell activation. Treatment of T~cells with pyrvinium pamoate early during their activation blocks an increase in mitochondrial mass and results in reduced proliferation, skewed CD4+ T~cell differentiation, and reduced cytokine production. Furthermore, administration of pyrvinium pamoate at the time of induction of experimental autoimmune encephalomyelitis, an experimental model of multiple sclerosis in mice, prevented the onset of clinical disease. Thus, modulation of mitochondrial biogenesis may provide a therapeutic strategy for modulating T~cell immune responses.},
	keywords = {Animals, CD4-Positive T-Lymphocytes, Encephalomyelitis, Autoimmune, Experimental, Lymphocyte Activation, Mice, Receptors, Antigen, T-Cell, T-Lymphocytes},
	issn = {2451-9448},
	doi = {10.1016/j.chembiol.2023.08.008},
	author = {Kurmi, Kiran and Liang, Dan and van de Ven, Robert and Georgiev, Peter and Gassaway, Brandon Mark and Han, SeongJun and Notarangelo, Giulia and Harris, Isaac S and Yao, Cong-Hui and Park, Joon Seok and Hu, Song-Hua and Peng, Jingyu and Drijvers, Jefte M and Boswell, Sarah and Sokolov, Artem and Dougan, Stephanie K and Sorger, Peter K and Gygi, Steven P and Sharpe, Arlene H and Haigis, Marcia C}
}
@article {1793236,
	title = {Microbiota-dependent regulation of costimulatory and coinhibitory pathways via innate immune sensors and implications for immunotherapy},
	journal = {Exp Mol Med},
	volume = {55},
	number = {9},
	year = {2023},
	month = {2023 Sep},
	pages = {1913-1921},
	abstract = {Our bodies are inhabited by trillions of microorganisms. The host immune system constantly interacts with the microbiota in barrier organs, including the intestines. Over decades, numerous studies have shown that our mucosal immune system is dynamically shaped by a variety of microbiota-derived signals. Elucidating the mediators of these interactions is an important step for understanding how the microbiota is linked to mucosal immune homeostasis and gut-associated diseases. Interestingly, the efficacy of cancer immunotherapies that manipulate costimulatory and coinhibitory pathways has been correlated with the gut microbiota. Moreover, adverse effects of these therapies in the gut are linked to dysregulation of the intestinal immune system. These findings suggest that costimulatory pathways in the immune system might serve as a bridge between the host immune system and the gut microbiota. Here, we review mechanisms by which commensal microorganisms signal immune cells and their potential impact on costimulation. We highlight how costimulatory pathways modulate the mucosal immune system through not only classical antigen-presenting cells but also innate lymphocytes, which are highly enriched in barrier organs. Finally, we discuss the adverse effects of immune checkpoint inhibitors in the gut and the possible relationship with the gut microbiota.},
	keywords = {Gastrointestinal Microbiome, Immune System, Immunity, Innate, Immunotherapy, Microbiota},
	issn = {2092-6413},
	doi = {10.1038/s12276-023-01075-0},
	author = {Park, Joon Seok and Gazzaniga, Francesca S and Kasper, Dennis L and Sharpe, Arlene H}
}
@article {1793211,
	title = {PD-1 Expression on Intratumoral Regulatory T Cells is Associated with Lack of Benefit from Anti-PD-1 Therapy in Metastatic Clear Cell Renal Cell Carcinoma Patients},
	journal = {Clin Cancer Res},
	year = {2023},
	month = {2023 Dec 07},
	abstract = {PURPOSE: PD-1 expression on CD8+TIM-3-LAG3- tumor-infiltrating cells predicts positive response to PD-1 blockade in metastatic clear cell renal cell carcinoma (mccRCC). Since PD-1 signaling inhibition in regulatory T cells (Tregs) augments their immunosuppressive function, we hypothesized that PD-1 expression on tumor-infiltrating Tregs would predict resistance to PD-1 inhibitors.

EXPERIMENTAL DESIGN: PD-1+ Tregs were phenotyped using multiparametric immunofluorescence in ccRCC tissues from the CheckMate-025 trial (nivolumab: n=91, everolimus: n=90). Expression of CD8, PD-1, TIM-3, and LAG-3 was previously determined (Ficial et al, 2021). Clinical endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).

RESULTS: In the nivolumab (but not everolimus) arm, high percentage of PD-1+ Tregs was associated with shorter PFS (3.19 versus 5.78 months; p=0.021), shorter OS (18.1 versus 27.7 months, p=0.013) and marginally lower ORR (12.5\% versus 31.3\%, p=0.059). An integrated biomarker (PD-1 Treg/CD8 ratio) was developed by calculating the ratio between percentage of PD-1+Tregs (marker of resistance) and percentage of CD8+PD-1+TIM-3-LAG-3- cells (marker of response). In the nivolumab (but not everolimus) arm, patients with high-PD-1 ratio experienced shorter PFS (3.48 versus 9.23 months, p\&lt;0.001), shorter OS (18.14 versus 38.21 months, p\&lt;0.001) and lower ORR (15.69\% versus 40.00\%; p=0.009). Compared to the individual biomarkers, the PD-1 ratio showed improved ability to predict outcomes to nivolumab versus everolimus.

CONCLUSIONS: PD-1 expression on Tregs is associated with resistance to PD-1 blockade in mccRCC, suggesting that targeting Tregs may synergize with PD-1 inhibition. A model that integrates PD-1 expression on Tregs and CD8+TIM-3-LAG3- cells has higher predictive value.},
	issn = {1557-3265},
	doi = {10.1158/1078-0432.CCR-23-2274},
	author = {Denize, Thomas and Jegede, Opeyemi A and Matar, Sayed and El Ahmar, Nourhan and West, Destiny J and Walton, Emily and Bagheri, Aseman Sheshdeh and Savla, Varunika and Nabil Laimon, Yasmin and Saurabh Gupta and Vemula, Sai Vikram and Braun, David A and Burke, Kelly P and Catalano, Paul J and Freeman, Gordon J and Motzer, Robert J and Atkins, Michael B and McDermott, David F and Sharpe, Arlene H and Choueiri, Toni K and Signoretti, Sabina}
}
@article {1793241,
	title = {Single-cell profiling reveals unique features of diabetogenic T cells in anti-PD-1-induced type 1 diabetes mice},
	journal = {J Exp Med},
	volume = {220},
	number = {10},
	year = {2023},
	month = {2023 Oct 02},
	abstract = {Immune-related adverse events (irAEs) are a notable complication of PD-1 cancer immunotherapy. A better understanding of how these iatrogenic diseases compare with naturally arising autoimmune diseases is needed for treatment and monitoring of irAEs. We identified differences in anti-PD-1-induced type 1 diabetes (T1D) and spontaneous T1D in non-obese diabetic (NOD) mice by performing single-cell RNA-seq and TCR-seq on T cells from the pancreas, pancreas-draining lymph node (pLN), and blood of mice with PD-1-induced T1D or spontaneous T1D. In the pancreas, anti-PD-1 resulted in expansion of terminally exhausted/effector-like CD8+ T cells, an increase in T-bethi CD4+FoxP3- T cells, and a decrease in memory CD4+FoxP3- and CD8+ T cells in contrast to spontaneous T1D. Notably, anti-PD-1 caused increased TCR sharing between the pancreas and the periphery. Moreover, T cells in the blood of anti-PD-1-treated mice expressed markers that differed from spontaneous T1D, suggesting that the blood may provide a window to monitor irAEs rather than relying exclusively on the autoimmune target organ.},
	keywords = {Animals, Diabetes Mellitus, Type 1, Forkhead Transcription Factors, Mice, Mice, Inbred NOD, Pancreas, Receptors, Antigen, T-Cell},
	issn = {1540-9538},
	doi = {10.1084/jem.20221920},
	author = {Collier, Jenna L and Pauken, Kristen E and Lee, Catherine A A and Patterson, Dillon G and Markson, Samuel C and Conway, Thomas S and Fung, Megan E and France, Joshua A and Mucciarone, Kyla N and Lian, Christine G and Murphy, George F and Sharpe, Arlene H}
}
@article {1793251,
	title = {Targeting PD-L2-RGMb overcomes microbiome-related immunotherapy resistance},
	journal = {Nature},
	volume = {617},
	number = {7960},
	year = {2023},
	month = {2023 May},
	pages = {377-385},
	abstract = {The gut microbiota is a crucial regulator of anti-tumour immunity during immune checkpoint inhibitor therapy. Several bacteria that promote an anti-tumour response to immune checkpoint inhibitors have been identified in mice1-6. Moreover, transplantation of faecal specimens from responders can improve the efficacy of anti-PD-1 therapy in patients with melanoma7,8. However, the increased efficacy from faecal transplants is variable and how gut bacteria promote anti-tumour immunity remains unclear. Here we show that the gut microbiome downregulates PD-L2 expression and its binding partner repulsive guidance molecule b (RGMb) to promote anti-tumour immunity and identify bacterial species that mediate this effect. PD-L1 and PD-L2 share PD-1 as a binding partner, but PD-L2 can also bind RGMb. We demonstrate that blockade of PD-L2-RGMb interactions can overcome microbiome-dependent resistance to PD-1 pathway inhibitors. Antibody-mediated blockade of the PD-L2-RGMb pathway or conditional deletion of RGMb in T cells combined with an anti-PD-1 or anti-PD-L1 antibody promotes anti-tumour responses in multiple mouse tumour models that do not respond to anti-PD-1 or anti-PD-L1 alone (germ-free mice, antibiotic-treated mice and even mice colonized with stool samples from a patient who did not respond to treatment). These studies identify downregulation of the PD-L2-RGMb pathway as a specific mechanism by which the gut microbiota can promote responses to PD-1 checkpoint blockade. The results also define a potentially effective immunological strategy for treating patients who do not respond to PD-1 cancer immunotherapy.},
	keywords = {Animals, Cell Adhesion Molecules, Neuronal, Disease Models, Animal, Down-Regulation, Drug Resistance, Neoplasm, Fecal Microbiota Transplantation, Germ-Free Life, Humans, Immune Checkpoint Inhibitors, Immunotherapy, Melanoma, Mice, Microbiota, Protein Binding, T-Lymphocytes},
	issn = {1476-4687},
	doi = {10.1038/s41586-023-06026-3},
	author = {Park, Joon Seok and Gazzaniga, Francesca S and Wu, Meng and Luthens, Amalia K and Gillis, Jacob and Zheng, Wen and LaFleur, Martin W and Johnson, Sarah B and Morad, Golnaz and Park, Elizabeth M and Zhou, Yifan and Watowich, Stephanie S and Wargo, Jennifer A and Freeman, Gordon J and Kasper, Dennis L and Sharpe, Arlene H}
}
@article {1793261,
	title = {Tracking tumor-specific CD8 T cell responses},
	journal = {Trends Immunol},
	volume = {44},
	number = {5},
	year = {2023},
	month = {2023 May},
	pages = {326-328},
	abstract = {In a recent article, Puig-Saus et al. computationally predict and experimentally validate neoantigen-specific T cell responses in patients with melanoma. They identify a restricted set of neoantigens recognized by polyclonal CD8+ T cells as a unique feature of anti-PD-1 responders and engineer autologous tumor-responsive T cells expressing neoantigen-specific TCRs, providing proof-of-concept for future cellular therapies.},
	keywords = {Antigens, Neoplasm, CD8-Positive T-Lymphocytes, Humans, Melanoma, Receptors, Antigen, T-Cell},
	issn = {1471-4981},
	doi = {10.1016/j.it.2023.03.012},
	author = {Burke, Kelly P and Markson, Samuel C and Sharpe, Arlene H}
}
@article {1793256,
	title = {Uncoupled glycerol-3-phosphate shuttle in kidney cancer reveals that cytosolic GPD is essential to support lipid synthesis},
	journal = {Mol Cell},
	volume = {83},
	number = {8},
	year = {2023},
	month = {2023 Apr 20},
	pages = {1340-1349.e7},
	abstract = {The glycerol-3-phosphate shuttle (G3PS) is a major NADH shuttle that regenerates reducing equivalents in the cytosol and produces energy in the mitochondria. Here, we demonstrate that G3PS is uncoupled in kidney cancer cells where the cytosolic reaction is \~{}4.5 times faster than the mitochondrial reaction. The high flux through cytosolic glycerol-3-phosphate dehydrogenase (GPD) is required to maintain redox balance and support lipid synthesis. Interestingly, inhibition of G3PS by knocking down mitochondrial GPD (GPD2) has no effect on mitochondrial respiration. Instead, loss of GPD2 upregulates cytosolic GPD on a transcriptional level and promotes cancer cell proliferation by increasing glycerol-3-phosphate supply. The proliferative advantage of GPD2 knockdown tumor can be abolished by pharmacologic inhibition of lipid synthesis. Taken together, our results suggest that G3PS is not required to run as an intact NADH shuttle but is instead truncated to support complex lipid synthesis in kidney cancer.},
	keywords = {Glycerol, Glycerol-3-Phosphate Dehydrogenase (NAD+), Glycerolphosphate Dehydrogenase, Humans, Kidney Neoplasms, Lipids, NAD, Oxidation-Reduction, Phosphates},
	issn = {1097-4164},
	doi = {10.1016/j.molcel.2023.03.023},
	author = {Yao, Cong-Hui and Park, Joon Seok and Kurmi, Kiran and Hu, Song-Hua and Notarangelo, Giulia and Crowley, Joseph and Jacobson, Heidi and Sheng Hui and Sharpe, Arlene H and Haigis, Marcia C}
}
@article {1793301,
	title = {CRISPR Screens to Identify Regulators of Tumor Immunity},
	journal = {Annu Rev Cancer Biol},
	volume = {6},
	year = {2022},
	month = {2022 Apr},
	pages = {103-122},
	abstract = {Cancer immunotherapies, such as immune checkpoint blockade (ICB), have been used in a wide range of tumor types with immense clinical benefit. However, ICB does not work in all patients, and attempts to combine ICB with other immune-based therapies have not lived up to their initial promise. Thus, there is a significant unmet need to discover new targets and combination therapies to extend the benefits of immunotherapy to more patients. Systems biology approaches are well suited for addressing this problem because these approaches enable evaluation of many gene targets simultaneously and ranking their relative importance for a phenotype of interest. As such, loss-of-function CRISPR screens are an emerging set of tools being used to prioritize gene targets for modulating pathways of interest in tumor and immune cells. This review describes the first screens performed to discover cancer immunotherapy targets and the technological advances that will enable next-generation screens.},
	issn = {2472-3428},
	doi = {10.1146/annurev-cancerbio-070120-094725},
	author = {LaFleur, Martin W and Sharpe, Arlene H}
}
@article {1793276,
	title = {Inactivation of Ebola Virus and SARS-CoV-2 in Cell Culture Supernatants and Cell Pellets by Gamma Irradiation},
	journal = {Viruses},
	volume = {15},
	number = {1},
	year = {2022},
	month = {2022 Dec 23},
	abstract = {Viral pathogens with the potential to cause widespread disruption to human health and society continue to emerge or re-emerge around the world. Research on such viruses often involves high biocontainment laboratories (BSL3 or BSL4), but the development of diagnostics, vaccines and therapeutics often uses assays that are best performed at lower biocontainment. Reliable inactivation is necessary to allow removal of materials to these spaces and to ensure personnel safety. Here, we validate the use of gamma irradiation to inactivate culture supernatants and pellets of cells infected with a representative member of the Filovirus and Coronavirus families. We show that supernatants and cell pellets containing SARS-CoV-2 are readily inactivated with 1.9 MRad, while Ebola virus requires higher doses of 2.6 MRad for supernatants and 3.8 MRad for pellets. While these doses of radiation inactivate viruses, proinflammatory cytokines that are common markers of virus infection are still detected with low losses. The doses required for virus inactivation of supernatants are in line with previously reported values, but the inactivation of cell pellets has not been previously reported and enables new approaches for analysis of protein-based host responses to infection.},
	keywords = {Cell Culture Techniques, COVID-19, Ebolavirus, Hemorrhagic Fever, Ebola, Humans, SARS-CoV-2, Virus Inactivation, Viruses},
	issn = {1999-4915},
	doi = {10.3390/v15010043},
	author = {Boytz, RuthMabel and Seitz, Scott and Gaudiano, Emily and Patten, J J and Keiser, Patrick T and Connor, John H and Sharpe, Arlene H and Davey, Robert A}
}
@article {1793286,
	title = {Oncometabolite d-2HG alters T cell metabolism to impair CD8 T cell function},
	journal = {Science},
	volume = {377},
	number = {6614},
	year = {2022},
	month = {2022 Sep 30},
	pages = {1519-1529},
	abstract = {Gain-of-function mutations in isocitrate dehydrogenase (IDH) in human cancers result in the production of d-2-hydroxyglutarate (d-2HG), an oncometabolite that promotes tumorigenesis through epigenetic alterations. The cancer cell-intrinsic effects of d-2HG are well understood, but its tumor cell-nonautonomous roles remain poorly explored. We compared the oncometabolite d-2HG with its enantiomer, l-2HG, and found that tumor-derived d-2HG was taken up by CD8+ T cells and altered their metabolism and antitumor functions in an acute and reversible fashion. We identified the glycolytic enzyme lactate dehydrogenase (LDH) as a molecular target of d-2HG. d-2HG and inhibition of LDH drive a metabolic program and immune CD8+ T cell signature marked by decreased cytotoxicity and impaired interferon-γ signaling that was recapitulated in clinical samples from human patients with IDH1 mutant gliomas.},
	keywords = {Animals, Carcinogenesis, CD8-Positive T-Lymphocytes, Gain of Function Mutation, Glutarates, Humans, Interferon-gamma, Isocitrate Dehydrogenase, L-Lactate Dehydrogenase, Mice, Neoplasms},
	issn = {1095-9203},
	doi = {10.1126/science.abj5104},
	author = {Notarangelo, Giulia and Spinelli, Jessica B and Perez, Elizabeth M and Baker, Gregory J and Kurmi, Kiran and Elia, Ilaria and Stopka, Sylwia A and Baquer, Gerard and Lin, Jia-Ren and Golby, Alexandra J and Joshi, Shakchhi and Baron, Heide F and Drijvers, Jefte M and Georgiev, Peter and Ringel, Alison E and Zaganjor, Elma and McBrayer, Samuel K and Sorger, Peter K and Sharpe, Arlene H and Wucherpfennig, Kai W and Santagata, Sandro and Agar, Nathalie Y R and Suv{\`a}, Mario L and Haigis, Marcia C}
}
@article {1793291,
	title = {PD-1 combination therapy with IL-2 modifies CD8 T cell exhaustion program},
	journal = {Nature},
	volume = {610},
	number = {7930},
	year = {2022},
	month = {2022 Oct},
	pages = {173-181},
	abstract = {Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection1. Here we examine the underlying basis for this synergy. We show that PD-1~+~IL-2 combination therapy, in contrast to PD-1 monotherapy, substantially changes the differentiation program of the PD-1+TCF1+ stem-like CD8+~T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8+~T cells that resemble highly functional effector CD8+~T cells seen after an acute viral infection. The generation of these qualitatively superior CD8+ T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1+TCF1+ stem-like CD8+ T cells, also referred to as precursors of exhausted CD8+ T cells, are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals. These virus-specific effector CD8+ T cells emerging from the stem-like CD8+ T cells after combination therapy expressed increased levels of the high-affinity IL-2 trimeric (CD25-CD122-CD132) receptor. This was not seen after PD-1 blockade alone. Finally, we show that CD25 engagement with IL-2 has an important role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind to CD25 but still binds to CD122 and CD132 almost completely abrogated the synergistic effects observed after PD-1~+~IL-2 combination therapy. There is considerable interest in PD-1~+~IL-2 combination therapy for patients with cancer2,3, and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies.},
	keywords = {CD8-Positive T-Lymphocytes, Cell Differentiation, Drug Therapy, Combination, Humans, Interleukin Receptor Common gamma Subunit, Interleukin-2, Interleukin-2 Receptor alpha Subunit, Interleukin-2 Receptor beta Subunit, Lymphocytic Choriomeningitis, Programmed Cell Death 1 Receptor, T Cell Transcription Factor 1},
	issn = {1476-4687},
	doi = {10.1038/s41586-022-05257-0},
	author = {Hashimoto, Masao and Araki, Koichi and Cardenas, Maria A and Li, Peng and Jadhav, Rohit R and Kissick, Haydn T and Hudson, William H and McGuire, Donald J and Obeng, Rebecca C and Wieland, Andreas and Lee, Judong and McManus, Daniel T and Ross, James L and Im, Se Jin and Lee, Junghwa and Lin, Jian-Xin and Hu, Bin and West, Erin E and Scharer, Christopher D and Freeman, Gordon J and Sharpe, Arlene H and Ramalingam, Suresh S and Pellerin, Alex and Teichgr{\"a}ber, Volker and Greenleaf, William J and Klein, Christian and Goronzy, Jorg J and Uma{\~n}a, Pablo and Leonard, Warren J and Smith, Kendall A and Ahmed, Rafi}
}
@article {1793296,
	title = {PD-L2 controls peripherally induced regulatory T cells by maintaining metabolic activity and Foxp3 stability},
	journal = {Nat Commun},
	volume = {13},
	number = {1},
	year = {2022},
	month = {2022 Aug 31},
	pages = {5118},
	abstract = {Regulatory T (Treg) cells are central to limit immune responses to allergens. Here we show that PD-L2 deficiency prevents the induction of tolerance to ovalbumin and control of airway hyperreactivity, in particular by limiting pTreg numbers and function. In vitro, PD-1/PD-L2 interactions increase iTreg numbers and stability. In mice lacking PD-L2 we find lower numbers of splenic pTregs at steady state, producing less IL-10 upon activation and with reduced suppressive activity. Remarkably, the numbers of splenic pTregs are restored by adoptively transferring PD-L2high dendritic cells to PD-L2KO mice. Functionally, activated pTregs lacking PD-L2 show lower Foxp3 expression, higher methylation of the Treg-Specific Demethylation Region (TSDR) and a decreased Tricarboxylic Acid (TCA) cycle associated with a defect in mitochondrial function and ATP production. Consequently, pyruvate treatment of PD-L2KO mice partially restores IL-10 production and airway tolerance. Together, our study highlights the importance of the PD-1/PD-L2 axis in the control of metabolic pathways regulating pTreg Foxp3 stability and suppressive functions, opening up avenues to further improve mucosal immunotherapy.},
	keywords = {Animals, Forkhead Transcription Factors, Interleukin-10, Mice, Ovalbumin, Programmed Cell Death 1 Ligand 2 Protein, Programmed Cell Death 1 Receptor, T-Lymphocytes, Regulatory},
	issn = {2041-1723},
	doi = {10.1038/s41467-022-32899-5},
	author = {Hurrell, Benjamin P and Helou, Doumet Georges and Howard, Emily and Painter, Jacob D and Shafiei-Jahani, Pedram and Sharpe, Arlene H and Akbari, Omid}
}
@article {article,
	title = {Repertoire analyses reveal T cell antigen receptor sequence features that influence T cell fate},
	journal = {Nature Immunology},
	volume = {23},
	year = {2022},
	month = {03},
	pages = {1-12},
	doi = {10.1038/s41590-022-01129-x},
	author = {Lagattuta, Kaitlyn and Kang, Joyce and Nathan, Aparna and Pauken, Kristen and Jonsson, Anna and Rao, Deepak and Sharpe, Arlene and Ishigaki, Kazuyoshi and Raychaudhuri, Soumya}
}
@article {article,
	title = {TCR-sequencing in cancer and autoimmunity: barcodes and beyond},
	journal = {Trends in Immunology},
	volume = {43},
	year = {2022},
	month = {01},
	doi = {10.1016/j.it.2022.01.002},
	author = {Pauken, Kristen and Lagattuta, Kaitlyn and Lu, Benjamin and Lucca, Liliana Elisa and Daud, Adil and Hafler, David and Kluger, Harriet and Raychaudhuri, Soumya and Sharpe, Arlene}
}
@article {article,
	title = {CRISPR Screens to Identify Regulators of Tumor Immunity},
	journal = {Annual Review of Cancer Biology},
	volume = {6},
	year = {2022},
	month = {04},
	doi = {10.1146/annurev-cancerbio-070120-094725},
	author = {LaFleur, Martin and Sharpe, Arlene}
}
@article {article,
	title = {Liver Stromal Cells Restrict Macrophage Maturation and Stromal IL-6 Limits the Differentiation of Cirrhosis-linked Macrophages},
	journal = {Journal of Hepatology},
	volume = {76},
	year = {2022},
	month = {01},
	doi = {10.1016/j.jhep.2021.12.036},
	author = {Buonomo, Erica and Mei, Shenglin and Guinn, Samantha and Leo, Isabelle and Peluso, Michael and Nolan, Mei-An and Schildberg, Frank and Zhao, Lei and Lian, Christine and Xu, Shuyun and Misdraji, Joseph and Kharchenko, Peter and Sharpe, Arlene}
}
@article {article,
	title = {Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8+ T cells},
	journal = {Cell Metabolism},
	volume = {34},
	year = {2022},
	month = {07},
	doi = {10.1016/j.cmet.2022.06.008},
	author = {Elia, Ilaria and Rowe, Jared and Johnson, Sheila and Joshi, Shakchhi and Notarangelo, Giulia and Kurmi, Kiran and Weiss, Sarah and Freeman, Gordon and Sharpe, Arlene and Haigis, Marcia}
}
@article {alvarez-breckenridge_microenvironmental_2022,
	title = {Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition},
	journal = {Cancer Immunology Research},
	volume = {10},
	number = {8},
	year = {2022},
	pages = {996{\textendash}1012},
	abstract = {Abstract Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.},
	issn = {2326-6066, 2326-6074},
	doi = {10.1158/2326-6066.CIR-21-0870},
	url = {https://aacrjournals.org/cancerimmunolres/article/10/8/996/707174/Microenvironmental-Landscape-of-Human-Melanoma},
	author = {Alvarez-Breckenridge, Christopher and Markson, Samuel C. and Stocking, Jackson H. and Nayyar, Naema and Lastrapes, Matt and Strickland, Matthew R. and Kim, Albert E. and de Sauvage, Magali and Dahal, Ashish and Larson, Juliana M. and Mora, Joana L. and Navia, Andrew W. and Klein, Robert H. and Kuter, Benjamin M. and Gill, Corey M. and Bertalan, Mia and Shaw, Brian and Kaplan, Alexander and Subramanian, Megha and Jain, Aarushi and Kumar, Swaminathan and Danish, Husain and White, Michael and Shahid, Osmaan and Pauken, Kristen E. and Miller, Brian C. and Frederick, Dennie T. and Hebert, Christine and Shaw, McKenzie and Martinez-Lage, Maria and Frosch, Matthew and Wang, Nancy and Gerstner, Elizabeth and Nahed, Brian V. and Curry, William T. and Carter, Bob and Cahill, Daniel P. and Boland, Genevieve Marie and Izar, Benjamin and Davies, Michael A. and Sharpe, Arlene H. and Suv{\`a}, Mario L. and Sullivan, Ryan J. and Brastianos, Priscilla K. and Carter, Scott L.}
}
@article {article,
	title = {The aging lung: Physiology, disease, and immunity},
	journal = {Cell},
	volume = {184},
	year = {2021},
	month = {04},
	doi = {10.1016/j.cell.2021.03.005},
	author = {Schneider, Jaime and Rowe, Jared and Garcia de Alba, Carolina and Kim, Carla and Sharpe, Arlene and Haigis, Marcia}
}
@article {article,
	title = {Progressive immune dysfunction with advancing disease stage in renal cell carcinoma},
	journal = {Cancer Cell},
	volume = {39},
	year = {2021},
	month = {03},
	doi = {10.1016/j.ccell.2021.02.013},
	author = {Braun, David and Street, Kelly and Burke, Kelly and Cookmeyer, David and Denize, Thomas and Pedersen, Christina Bligaard and Gohil, Satyen and Schindler, Nicholas and Pomerance, Lucas and Hirsch, Laure and Bakouny, Ziad and Hou, Yue and Forman, Juliet and Huang, Teddy and Li, Shuqiang and Cui, Ang and Keskin, Derin and Steinharter, John and Bouchard, Gabrielle and Wu, Catherine}
}
@article {article,
	title = {Epitope spreading toward wild-type melanocyte-lineage antigens rescues suboptimal immune checkpoint blockade responses},
	journal = {Science Translational Medicine},
	volume = {13},
	year = {2021},
	month = {02},
	pages = {eabd8636},
	doi = {10.1126/scitranslmed.abd8636},
	author = {Lo, Jennifer and Kawakubo, Masayoshi and Juneja, Vikram and Su, Mack and Erlich, Tal and LaFleur, Martin and Kem{\'e}ny, Lajos and Rashid, Mamunur and Malehmir, Mohsen and Rabi, S. and Raghavan, Rumya and Allouche, Jennifer and Kasumova, Gyulnara and Frederick, Dennie and Pauken, Kristen and Weng, Qing and Silva, Marcelo and Xu, Yu and Sande, Anita and Fisher, David}
}
@article {article,
	title = {Emerging concepts in PD-1 checkpoint biology},
	journal = {Seminars in Immunology},
	volume = {52},
	year = {2021},
	month = {05},
	pages = {101480},
	doi = {10.1016/j.smim.2021.101480},
	author = {Pauken, Kristen and Torchia, James and Chaudhri, Apoorvi and Sharpe, Arlene and Freeman, Gordon}
}
@article {article,
	title = {Not-so-opposite ends of the spectrum: CD8+ T cell dysfunction across chronic infection, cancer and autoimmunity},
	journal = {Nature Immunology},
	volume = {22},
	year = {2021},
	month = {06},
	pages = {1-11},
	doi = {10.1038/s41590-021-00949-7},
	author = {Collier, Jenna and Weiss, Sarah and Pauken, Kristen and Sen, Debattama and Sharpe, Arlene}
}
@article {article,
	title = {Single-cell analyses identify circulating anti-tumor CD8 T cells and markers for their enrichment},
	journal = {Journal of Experimental Medicine},
	volume = {218},
	year = {2021},
	month = {03},
	doi = {10.1084/jem.20200920},
	author = {Pauken, Kristen and Shahid, Osmaan and Lagattuta, Kaitlyn and Mahuron, Kelly and Luber, Jacob and Lowe, Margaret and Huang, Linglin and Conor Delaney and Long, Jaclyn and Fung, Megan and Newcomer, Kathleen and Tsai, Katy and Chow, Melissa and Guinn, Samantha and Kuchroo, Juhi and Burke, Kelly and Schenkel, Jason and Rosenblum, Michael and Daud, Adil and Singer, Meromit}
}
@article {article,
	title = {The double-edged sword: Harnessing PD-1 blockade in tumor and autoimmunity},
	journal = {Science immunology},
	volume = {6},
	year = {2021},
	month = {11},
	pages = {eabf4034},
	doi = {10.1126/sciimmunol.abf4034},
	author = {Kuchroo, Juhi and Hafler, David and Sharpe, Arlene and Lucca, Liliana Elisa}
}
@article {article,
	title = {The PD-1 Pathway Regulates Development and Function of Memory CD8+ T Cells following Respiratory Viral Infection},
	journal = {Cell Reports},
	volume = {31},
	year = {2020},
	month = {06},
	pages = {107827},
	doi = {10.1016/j.celrep.2020.107827},
	author = {Pauken, Kristen and Godec, Jernej and Odorizzi, Pamela and Brown, Keturah and Yates, Kathleen and Ngiow, Shin and Burke, Kelly and Maleri, Seth and Grande, Shannon and Francisco, Loise and Ali, Mohammed-Alkhatim and Imam, Sabrina and Freeman, Gordon and Haining, W. and Wherry, E. John and Sharpe, Arlene}
}
@article {article,
	title = {Pharmacologic Screening Identifies Metabolic Vulnerabilities of CD8+ T Cells},
	journal = {Cancer Immunology Research},
	volume = {9},
	year = {2020},
	month = {12},
	pages = {canimm.0384.2020},
	doi = {10.1158/2326-6066.CIR-20-0384},
	author = {Drijvers, Jefte and Gillis, Jacob and Muijlwijk, Tara and Nguyen, Thao and Gaudiano, Emily and Isaac Harris and LaFleur, Martin and Ringel, Alison and Yao, Cong-Hui and Kurmi, Kiran and Juneja, Vikram and Trombley, Justin and Haigis, Marcia and Sharpe, Arlene}
}
@article {article,
	title = {Understanding adverse events of immunotherapy: A mechanistic perspective},
	journal = {Journal of Experimental Medicine},
	volume = {218},
	year = {2020},
	month = {12},
	doi = {10.1084/jem.20192179},
	author = {Burke, Kelly and Grebinoski, Stephanie and Sharpe, Arlene and Vignali, Dario}
}
@article {article,
	title = {The multifaceted functions of follicular regulatory T cells},
	journal = {Current Opinion in Immunology},
	volume = {67},
	year = {2020},
	month = {12},
	pages = {68-74},
	doi = {10.1016/j.coi.2020.10.009},
	author = {Sage, Peter and Sharpe, Arlene}
}
@article {article,
	title = {The effects of age and systemic metabolism on anti-tumor T cell responses},
	journal = {eLife},
	volume = {9},
	year = {2020},
	month = {11},
	doi = {10.7554/eLife.62420},
	author = {Drijvers, Jefte and Sharpe, Arlene and Haigis, Marcia}
}
@article {article,
	title = {PD-1 restraint of regulatory T cell suppressive activity is critical for immune tolerance},
	journal = {Journal of Experimental Medicine},
	volume = {218},
	year = {2020},
	month = {10},
	doi = {10.1084/jem.20182232},
	author = {Tan, Catherine and Kuchroo, Juhi and Sage, Peter and Liang, Dan and Francisco, Loise and Buck, Jessica and Thaker, Youg and Zhang, Qianxia and McArdel, Shannon and Juneja, Vikram and Lee, Sun and Lovitch, Scott and Lian, Christine and Murphy, George and Blazar, Bruce and Vignali, Dario and Freeman, Gordon and Sharpe, Arlene}
}
@article {1527668,
	title = {The PD-1 Pathway Regulates Development and Function of Memory CD8+ T Cells following Respiratory Viral Infection},
	journal = {Cell Reports},
	volume = {31},
	number = {13},
	year = {2020},
	pages = {107827},
	abstract = {
	The PD-1 pathway regulates dysfunctional T cells in chronic infection and cancer, but the role of this pathway during acute infection remains less clear. Here, we demonstrate that PD-1 signals are needed for optimal memory. Mice deficient in the PD-1 pathway exhibit impaired CD8+ T cell memory following acute influenza infection, including reduced virus-specific CD8+ T cell numbers and compromised recall responses. PD-1 blockade during priming leads to similar differences early post-infection but without the defect in memory formation, suggesting that timing and/or duration of PD-1 blockade could be tailored to modulate host responses. Our studies reveal a role for PD-1 as an integrator of CD8+ T cell signals that promotes CD8+ T cell memory formation and suggest PD-1 continues to fine-tune CD8+ T cells after they migrate into nonlymphoid tissues. These findings have important implications for PD-1-based immunotherapy, in which PD-1 inhibition may influence memory responses in patients.



	PubMed\&nbsp;DOI

},
	author = {Pauken, KE and Godec, J and Odorizzi, PM and Brown, KE and Yates, KB and Ngiow, SF and Burke, KP and Freeman, G. J. and Haining, WN and Wherry, EJ and Sharpe, A. H.}
}
@article {1527665,
	title = {Prevention of CAR-T-cell dysfunction},
	journal = {Nat Biomed Eng},
	volume = {4},
	number = {1},
	year = {2020},
	pages = {16-17},
	abstract = {
	The overexpression of the transcription factor c-Jun improves chimeric-antigen-receptor T-cell functionality and enhances the killing of low-antigen-expressing liquid and solid cancers in mice.



	PubMed\&nbsp;DOI

},
	author = {LaFleur, MW and Miller, BC and Sharpe, A. H.}
}
@article {1527663,
	title = {Fibroblastic reticular cells enhance T cell metabolism and survival via epigenetic remodeling},
	journal = {Nature Immunology},
	volume = {20},
	number = {12},
	year = {2019},
	pages = {1668-1680},
	abstract = {
	Lymph node fibroblastic reticular cells (FRCs) respond to signals from activated T cells by releasing nitric oxide, which inhibits T cell proliferation and restricts the size of the expanding T cell pool. Whether interactions with FRCs also support the function or differentiation of activated CD8+\&nbsp;T cells is not known. Here we report that encounters with FRCs enhanced cytokine production and remodeled chromatin accessibility in newly activated CD8+\&nbsp;T cells via interleukin-6. These epigenetic changes facilitated metabolic reprogramming and amplified the activity of pro-survival pathways through differential transcription factor activity. Accordingly, FRC conditioning significantly enhanced the persistence of virus-specific CD8+\&nbsp;T cells in vivo and augmented their differentiation into tissue-resident memory T cells. Our study demonstrates that FRCs play a role beyond restricting T cell expansion{\textemdash}they can also shape the fate and function of CD8+\&nbsp;T cells.



	PubMed\&nbsp;DOI

},
	author = {Brown, FD and Sen, DR and LaFleur, MW and Godec, J and Lukacs-Kornek, V and Danial, NN and Manning, BD and Sharpe, A. H. and Haining, WN and Turley, SJ}
}
@article {1527658,
	title = {T Cell Activation Depends on Extracellular Alanine},
	journal = {Cell Reports},
	volume = {28},
	number = {12},
	year = {2019},
	pages = {3011-3021},
	abstract = {
	T cell stimulation is metabolically demanding. To exit quiescence, T\&nbsp;cells rely on environmental nutrients, including glucose and the amino acids glutamine, leucine, serine, and arginine. The expression of transporters for these nutrients is tightly regulated and required for T\&nbsp;cell activation. In contrast to these amino acids, which are essential or require multi-step biosynthesis, alanine can be made from pyruvate by a single transamination. Here, we show that extracellular alanine is nevertheless required for efficient exit from quiescence during naive T\&nbsp;cell activation and memory T\&nbsp;cell restimulation. Alanine deprivation leads to metabolic and functional impairments. Mechanistically, this vulnerability reflects the low expression of alanine aminotransferase, the enzyme required for interconverting pyruvate and alanine, whereas activated T\&nbsp;cells instead induce alanine transporters. Stable isotope tracing reveals that alanine is not catabolized but instead supports protein synthesis. Thus, T\&nbsp;cells depend on exogenous alanine for protein synthesis and normal activation.



	PubMed\&nbsp;DOI

},
	author = {Ron-Harel, N and Ghergurovich, JM and Notarangelo, G and LaFleur, MW and Tsubosaka, Y and Sharpe, A. H. and Rabinowitz, JD and Haigis, MC}
}
@article {1527657,
	title = {Immuno-PET identifies the myeloid compartment as a key contributor to the outcome of the antitumor response under PD-1 blockade},
	journal = {PNAS},
	volume = {116},
	number = {34},
	year = {2019},
	pages = {16971-16980},
	abstract = {
	Immunotherapy, especially blockade of the PD-1/PD-L1 and CTLA-4 axes, has resulted in durable responses in a range of cancers. However, responses remain heterogeneous among patients. Treatment outcome results from changes in the tumor microenvironment imposed by such blockade. Here, we use immuno-PET and single-cell RNA sequencing to increase our understanding of the dynamics of immune cells and their functional status in the tumor microenvironment in response to PD-1 blockade. Our data provide insights into the dynamics of CD8+\&nbsp;T cells and the functional status of the myeloid compartment in response to PD-1 blockade.



	PubMed\&nbsp;DOI

},
	author = {Rashidian, M and LaFleur, MW and Verschoor, VL and Dongre, A and Zhang, Y. and Nguyen, TH and Kolifrath, S and Aref, AR and Lau, CJ and Paweletz, CP and Bu, X and Freeman, G. J. and Barrasa, MI and Weinberg, RA and Sharpe, A. H. and Ploegh, H.L.}
}
@article {1527654,
	title = {PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity},
	journal = {Nature Immunology},
	volume = {20},
	number = {10},
	year = {2019},
	pages = {1335-1347},
	abstract = {
	CD8+\&nbsp;T cell exhaustion is a state of dysfunction acquired in chronic viral infection and cancer, characterized by the formation of Slamf6+\&nbsp;progenitor exhausted and Tim-3+\&nbsp;terminally exhausted subpopulations through unknown mechanisms. Here we establish the phosphatase PTPN2 as a new regulator of the differentiation of the terminally exhausted subpopulation that functions by attenuating type 1 interferon signaling. Deletion of\&nbsp;Ptpn2\&nbsp;in CD8+\&nbsp;T cells increased the generation, proliferative capacity and cytotoxicity of Tim-3+\&nbsp;cells without altering Slamf6+\&nbsp;numbers during lymphocytic choriomeningitis virus clone 13 infection. Likewise, Ptpn2\&nbsp;deletion in CD8+\&nbsp;T cells enhanced Tim-3+\&nbsp;anti-tumor responses and improved tumor control. Deletion of\&nbsp;Ptpn2\&nbsp;throughout the immune system resulted in MC38 tumor clearance and improved programmed cell death-1 checkpoint blockade responses to B16 tumors. Our results indicate that increasing the number of cytotoxic Tim-3+CD8+\&nbsp;T cells can promote effective anti-tumor immunity and implicate PTPN2 in immune cells as an attractive cancer immunotherapy target.



	PubMed\&nbsp;DOI

},
	author = {LaFleur, MW and Nguyen, TH and Coxe, MA and Miller, BC and Yates, KB and Gaudiano, EF and Sen, DR and Gillis, JE and Al Abosy, R and Freeman, G. J. and Haining, WN and Sharpe, A. H.}
}
@article {1447141,
	title = {Adverse Events Following Cancer Immunotherapy: Obstacles and Opportunities},
	journal = {Trends Immunol},
	volume = {40},
	number = {6},
	year = {2019},
	pages = {511-523},
	abstract = {
	Oncology has recently undergone a revolutionary change with widespread adoption of immunotherapy for many cancers. Immunotherapy using monoclonal antibodies against checkpoint molecules, including programmed death (PD)-1, PD ligand (PD-L)1, and cytotoxic T lymphocyte-associated antigen (CTLA)-4, is effective in a significant subset of patients. However, immune-related adverse events (irAEs) have emerged as frequent complications of checkpoint blockade, likely due to the physiological role of checkpoint pathways in regulating adaptive immunity and preventing autoimmunity. As immunotherapy becomes more common, a better understanding of the etiology of irAEs and ways to limit these events is needed. At the same time, studying these new therapy-related disorders provides an opportunity to better understand naturally occurring human autoimmune and inflammatory disorders, with the potential to improve therapies for cancer and autoimmune diseases.



	PubMed\&nbsp;DOI

},
	author = {Pauken, KE and Dougan, M and Rose, NR and Lichtman, AH and Sharpe, A. H.}
}
@article {1432002,
	title = {FoxP3 and Ezh2 regulate Tfr cell suppressive function and transcriptional program},
	journal = {J Exp Med},
	volume = {216},
	number = {3},
	year = {2019},
	pages = {605-620},
	abstract = {
	Follicular regulatory T (Tfr) cells are a regulatory T cell subset that controls antibody production by inhibiting T follicular helper (Tfh)-mediated help to B cells. Tfh and Tfr cells possess opposing functions suggesting unique programming. Here we elucidated the transcriptional program controlling Tfr suppressive function. We found that Tfr cells have a program for suppressive function fine-tuned by tissue microenvironment. The transcription factor FoxP3 and chromatin-modifying enzyme EZH2 are essential for this transcriptional program but regulate the program in distinct ways. FoxP3 modifies the Tfh program to induce a Tfr-like functional state, demonstrating that Tfr cells coopt the Tfh program for suppression. Importantly, we identified a Tfr cell population that loses the Tfr program to become "ex-Tfr" cells with altered functionality. These dysfunctional ex-Tfr cells may have roles in modulating pathogenic antibody responses. Taken together, our studies reveal mechanisms controlling the Tfr transcriptional program and how failure of these mechanisms leads to dysfunctional Tfr cells.



	PubMed\&nbsp;DOI

},
	author = {Hou, Shenda and Clement, Rachel L and Diallo, Alos and Blazar, Bruce R and Rudensky, Alexander Y and Sharpe, Arlene H and Sage, Peter T}
}
@article {1431998,
	title = {Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade},
	journal = {Nat Immunol},
	volume = {20},
	number = {3},
	year = {2019},
	abstract = {
	T cell dysfunction is a hallmark of many cancers, but the basis for T cell dysfunction and the mechanisms by which antibody blockade of the inhibitory receptor PD-1 (anti-PD-1) reinvigorates T cells are not fully understood. Here we show that such therapy acts on a specific subpopulation of exhausted CD8+ tumor-infiltrating lymphocytes (TILs). Dysfunctional CD8+ TILs possess canonical epigenetic and transcriptional features of exhaustion that mirror those seen in chronic viral infection. Exhausted CD8+ TILs include a subpopulation of {\textquoteleft}progenitor exhausted{\textquoteright} cells that retain polyfunctionality, persist long term and differentiate into {\textquoteleft}terminally exhausted{\textquoteright} TILs. Consequently, progenitor exhausted CD8+ TILs are better able to control tumor growth than are terminally exhausted T cells. Progenitor exhausted TILs can respond to anti-PD-1 therapy, but terminally exhausted TILs cannot. Patients with melanoma who have a higher percentage of progenitor exhausted cells experience a longer duration of response to checkpoint-blockade therapy. Thus, approaches to expand the population of progenitor exhausted CD8+ T cells might be an important component of improving the response to checkpoint blockade.



	PubMed\&nbsp;DOI

},
	author = {Miller, Brian C and Sen, Debattama R and Abosy, Rose Al and Bi, Kevin and Virkud, Yamini V and LaFleur, Martin W and Yates, Katleen B and Rodig, Scott K and Sharpe, Arlene H and Haining, W Nicholas and et al.}
}
@article {1293161,
	title = {A CRISPR-Cas9 delivery system for in vivo screening of genes in the immune system},
	journal = {Nat Commun},
	volume = {10},
	number = {1668},
	year = {2019},
	month = {2018 Jan 15},
	abstract = {
	Therapies that target the function of immune cells have significant clinical efficacy in diseases such as cancer and autoimmunity. Although functional genomics has accelerated therapeutic target discovery in cancer, its use in primary immune cells is limited because vector delivery is inefficient and can perturb cell states. Here we describe CHIME: CHimeric IMmune Editing, a CRISPR-Cas9 bone marrow delivery system to rapidly evaluate gene function in innate and adaptive immune cells in vivo without ex vivo manipulation of these mature lineages. This approach enables efficient deletion of genes of interest in major immune lineages without altering their development or function. We use this approach to perform an in vivo pooled genetic screen and identify Ptpn2 as a negative regulator of CD8+ T cell-mediated responses to LCMV Clone 13 viral infection. These findings indicate that this genetic platform can enable rapid target discovery through pooled screening in immune cells in vivo.



	PubMed\&nbsp;DOI

},
	issn = {1550-6606},
	doi = {10.4049/jimmunol.1701076},
	author = {LaFleur, Martin W and Nguyen, Thao H and Coxe, Matthew A and Yates, Kathleen B and Trombley, Justin D and Weiss, Sarah A and Brown, Flavian D and Gillis, Jacob E and Coxe, Daniel J and Deonch, John G and Haining, W Nicholas and Sharpe, Arlene H}
}
@article {1527673,
	title = {LSD1 Ablation Stimulates Anti-tumor Immunity and Enables Checkpoint Blockade},
	journal = {Cell},
	volume = {174},
	number = {3},
	year = {2018},
	pages = {549-563},
	abstract = {
	Chromatin regulators play a broad role in regulating gene expression and, when gone awry, can lead to cancer. Here, we demonstrate that ablation of the histone demethylase LSD1 in cancer cells increases repetitive element expression, including endogenous retroviral elements (ERVs), and decreases expression of RNA-induced silencing complex (RISC) components. Significantly, this leads to double-stranded RNA (dsRNA) stress and activation of type 1 interferon, which stimulates anti-tumor T cell immunity and restrains tumor growth. Furthermore, LSD1 depletion enhances tumor immunogenicity and T cell infiltration in poorly immunogenic tumors and elicits significant responses of checkpoint blockade-refractory mouse melanoma to anti-PD-1 therapy. Consistently, TCGA data analysis shows an inverse correlation between LSD1 expression and CD8+\&nbsp;T cell infiltration in various human cancers. Our study identifies LSD1 as a potent inhibitor of anti-tumor immunity and responsiveness to immunotherapy and suggests LSD1 inhibition combined with PD-(L)1 blockade as a novel cancer treatment strategy.



	PubMed\&nbsp;DOI

},
	author = {Sheng, W and LaFleur, MW and Nguyen, TH and Chen, S. and Chakravarthy, A and Freeman, G. J. and Carvalho, DD and He, HH and Sharpe, A. H. and Shi, Y}
}
@article {1432023,
	title = {CD160 Stimulates CD8+ T Cell Responses and Is Required for Optimal Protective Immunity to Listeria monocytogenes},
	journal = {ImmunoHorizons},
	volume = {2},
	number = {7},
	year = {2018},
	pages = {238-250},
	abstract = {
	CD160 promotes NK cell cytotoxicity and IFN-γ production, but the function of CD160 on CD8+T cells remains unclear with some studies supporting a coinhibitory role and others a costimulatory role. In this study, we demonstrate that CD160 has a costimulatory role in promoting CD8+\&nbsp;T cell effector functions needed for optimal clearance of oral\&nbsp;Listeria monocytogenes\&nbsp;infection. CD160-/-\&nbsp;mice did not clear oral\&nbsp;L. monocytogenes\&nbsp;as efficiently as wild type (WT) littermates. WT RAG-/-\&nbsp;and CD160-/-\&nbsp;RAG-/-\&nbsp;mice similarly cleared\&nbsp;L. monocytogenes, indicating that CD160 on NK cells does not contribute to impaired\&nbsp;L. monocytogenes\&nbsp;clearance. Defective\&nbsp;L. monocytogenes\&nbsp;clearance is due to compromised intraepithelial lymphocytes and CD8+\&nbsp;T cell functions. There was a reduction in the frequencies of granzyme B{\textendash}expressing intraepithelial lymphocytes in\&nbsp;L. monocytogenes{\textendash}infected CD160-/-mice as compared with WT littermate controls. Similarly, the frequencies of granzyme B{\textendash}expressing splenic CD8+\&nbsp;T cells and IFN-γ and TNF-α double-producer CD8+\&nbsp;T cells were significantly reduced in\&nbsp;L. monocytogenes{\textendash}infected CD160-/-\&nbsp;mice compared with WT littermates. Adoptive transfer studies showed that RAG-/-\&nbsp;recipients receiving CD160-/-\&nbsp;CD8+\&nbsp;T cells had a higher mortality, exhibited more weight loss, and had a higher bacterial burden compared with RAG-/-\&nbsp;recipients receiving WT CD8+\&nbsp;T cells. These findings demonstrate that CD160 provides costimulatory signals to CD8+\&nbsp;T cells needed for optimal CD8+\&nbsp;T cell responses and protective immunity during an acute mucosal bacterial infection.



	PubMed\&nbsp;DOI

},
	author = {Tan, Catherine L and Peluso, Michael J and Drivjers, Jefte M and Mera, Camila M and Grande, Shannon M and Brown, Keturah E and Godec, Jernej and Freeman, Gordon J and Sharpe, Arlene H}
}
@article {1293159,
	title = {Inhibitors of the PD-1 Pathway in Tumor Therapy},
	journal = {J Immunol},
	volume = {200},
	number = {2},
	year = {2018},
	month = {2018 Jan 15},
	pages = {375-383},
	abstract = {
	The programmed death 1 (PD-1) pathway delivers inhibitory signals that function as a brake for immune responses. This pathway limits the initiation and duration of immune responses, thereby protecting tissues from immune-mediated damage and autoimmune diseases. However, the PD-1 pathway also inhibits immune responses to tumors. The critical role of PD-1 in preventing antitumor immunity is demonstrated by the transformative effects of PD-1 pathway blockade in a broad range of cancers with the hallmark of durability of response. Despite this success, most patients do not respond to PD-1 monotherapy, and some patients experience adverse events. In this review, we discuss the functions of the PD-1 pathway and its translation to cancer immunotherapy. We also consider current challenges and opportunities for PD-1 cancer immunotherapy, including mechanisms of response and resistance, identification of biomarkers of response to PD-1 therapy, characterization and treatment of PD-1 therapy-related adverse events, and development of safe and effective combination therapies.



	PubMed\&nbsp;DOI

},
	issn = {1550-6606},
	doi = {10.4049/jimmunol.1701044},
	author = {LaFleur, Martin W and Muroyama, Yuki and Drake, Charles G and Sharpe, Arlene H}
}
@article {1447140,
	title = {The diverse functions of the PD1 inhibitory pathway},
	journal = {Nat Rev Immunol},
	volume = {18},
	number = {3},
	year = {2017},
	pages = {153-167},
	abstract = {
	T cell activation is a highly regulated process involving peptide-MHC engagement of the T cell receptor and positive costimulatory signals. Upon activation, coinhibitory {\textquoteright}checkpoints{\textquoteright}, including programmed cell death protein 1 (PD1), become induced to regulate T cells. PD1 has an essential role in balancing protective immunity and immunopathology, homeostasis and tolerance. However, during responses to chronic pathogens and tumours, PD1 expression can limit protective immunity. Recently developed PD1 pathway inhibitors have revolutionized cancer treatment for some patients, but the majority of patients do not show complete responses, and adverse events have been noted. This Review discusses the diverse roles of the PD1 pathway in regulating immune responses and how this knowledge can improve cancer immunotherapy as well as restore and/or maintain tolerance during autoimmunity and transplantation.



	PubMed\&nbsp;DOI

},
	author = {Sharpe, A. H. and Pauken, KE}
}
@article {1293162,
	title = {B Cells Drive Autoimmunity in Mice with CD28-Deficient Regulatory T Cells},
	journal = {J Immunol},
	volume = {199},
	number = {12},
	year = {2017},
	month = {2017 Dec 15},
	pages = {3972-3980},
	abstract = {
	Follicular regulatory T (TFR) cells are a newly defined regulatory T cell (Treg) subset that suppresses follicular helper T cell-mediated B cell responses in the germinal center reaction. The precise costimulatory signal requirements for proper TFR cell differentiation and function are still not known. Using conditional knockout strategies of CD28, we previously demonstrated that loss of CD28 signaling in Tregs caused autoimmunity in mice (termed CD28-ΔTreg mice), characterized by lymphadenopathy, accumulation of activated T cells, and cell-mediated inflammation of the skin and lung. In this study, we show that CD28 signaling is required for TFR cell differentiation. Treg-specific deletion of CD28 caused a reduction in TFR cell numbers and function, which resulted in increased germinal center B cells and Ab production. Moreover, residual CD28-deficient TFR cells showed a diminished suppressive capacity as assessed by their ability to inhibit Ab responses in vitro. Surprisingly, genetic deletion of B cells in CD28-ΔTreg mice prevented the development of lymphadenopathy and CD4+ T cell activation, and autoimmunity that mainly targeted skin and lung tissues. Thus, autoimmunity occurring in mice with CD28-deficient Tregs appears to be driven primarily by loss of TFR cell differentiation and function with resulting B cell-driven inflammation.



	PubMed\&nbsp;DOI

},
	keywords = {Animals, Antibody Formation, Autoimmune Diseases, Autoimmunity, B-Lymphocytes, CD28 Antigens, CD4-Positive T-Lymphocytes, Cytokines, Female, Germinal Center, Immune Tolerance, Lung, Lymphadenopathy, Lymphocyte Depletion, Lymphopoiesis, Mice, Organ Specificity, Skin, Specific Pathogen-Free Organisms, T-Lymphocyte Subsets, T-Lymphocytes, Regulatory},
	issn = {1550-6606},
	doi = {10.4049/jimmunol.1700409},
	author = {Zhang, Ruan and Sage, Peter T and Finn, Kelsey and Huynh, Alexandria and Blazar, Bruce R and Marangoni, Francesco and Mempel, Thorsten R and Sharpe, Arlene H and Turka, Laurence A}
}
@article {1051296,
	title = {Introduction to checkpoint inhibitors and cancer immunotherapy},
	journal = {Immunol Rev},
	volume = {276},
	number = {1},
	year = {2017},
	month = {2017 Mar},
	pages = {5-8},
	abstract = {PubMed},
	issn = {1600-065X},
	doi = {10.1111/imr.12531},
	author = {Sharpe, Arlene H}
}
@article {1051276,
	title = {Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent},
	journal = {Science},
	volume = {355},
	number = {6332},
	year = {2017},
	month = {2017 Mar 31},
	pages = {1423-1427},
	abstract = {
	Programmed cell death-1 (PD-1)-targeted therapies enhance T cell responses and show efficacy in multiple cancers, but the role of costimulatory molecules in this T cell rescue remains elusive. Here, we demonstrate that the CD28/B7 costimulatory pathway is essential for effective PD-1 therapy during chronic viral infection. Conditional gene deletion showed a cell-intrinsic requirement of CD28 for CD8 T cell proliferation after PD-1 blockade. B7-costimulation was also necessary for effective PD-1 therapy in tumor-bearing mice. In addition, we found that CD8 T cells proliferating in blood after PD-1 therapy of lung cancer patients were predominantly CD28-positive. Taken together, these data demonstrate CD28-costimulation requirement for CD8 T cell rescue and suggest an important role for the CD28/B7 pathway in PD-1 therapy of cancer patients.



	PubMed\&nbsp;DOI

},
	issn = {1095-9203},
	doi = {10.1126/science.aaf0683},
	author = {Kamphorst, Alice O and Wieland, Andreas and Nasti, Tahseen and Yang, Shu and Zhang, Ruan and Barber, Daniel L and Konieczny, Bogumila T and Daugherty, Candace Z and Koenig, Lydia and Yu, Ke and Sica, Gabriel L and Sharpe, Arlene H and Freeman, Gordon J and Blazar, Bruce R and Turka, Laurence A and Owonikoko, Taofeek K and Pillai, Rathi N and Ramalingam, Suresh S and Araki, Koichi and Ahmed, Rafi}
}
@article {1051246,
	title = {PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity},
	journal = {J Exp Med},
	volume = {214},
	number = {4},
	year = {2017},
	month = {2017 Apr 03},
	pages = {895-904},
	abstract = {
	It is unclear whether PD-L1 on tumor cells is sufficient for tumor immune evasion or simply correlates with an inflamed tumor microenvironment. We used three mouse tumor models sensitive to PD-1 blockade to evaluate the significance of PD-L1 on tumor versus nontumor cells. PD-L1 on nontumor cells is critical for inhibiting antitumor immunity in B16 melanoma and a genetically engineered melanoma. In contrast, PD-L1 on MC38 colorectal adenocarcinoma cells is sufficient to suppress antitumor immunity, as deletion of PD-L1 on highly immunogenic MC38 tumor cells allows effective antitumor immunity. MC38-derived PD-L1 potently inhibited CD8(+) T cell cytotoxicity. Wild-type MC38 cells outcompeted PD-L1-deleted MC38 cells in vivo, demonstrating tumor PD-L1 confers a selective advantage. Thus, both tumor- and host-derived PD-L1 can play critical roles in immunosuppression. Differences in tumor immunogenicity appear to underlie their relative importance. Our findings establish reduced cytotoxicity as a key mechanism by which tumor PD-L1 suppresses antitumor immunity and demonstrate that tumor PD-L1 is not just a marker of suppressed antitumor immunity.



	PubMed\&nbsp;DOI

},
	issn = {1540-9538},
	doi = {10.1084/jem.20160801},
	author = {Juneja, Vikram R and McGuire, Kathleen A and Manguso, Robert T and LaFleur, Martin W and Collins, Natalie and Haining, W Nicholas and Freeman, Gordon J and Sharpe, Arlene H}
}
@article {1051421,
	title = {Programmed Death-1 Ligand 2-Mediated Regulation of the PD-L1 to PD-1 Axis Is Essential for Establishing CD4(+) T Cell Immunity},
	journal = {Immunity},
	volume = {45},
	number = {2},
	year = {2016},
	month = {2016 Aug 16},
	pages = {333-45},
	abstract = {Many pathogens, including Plasmodium spp., exploit the interaction of programmed death-1 (PD-1) with PD-1-ligand-1 (PD-L1) to "deactivate" T~cell functions, but the role of PD-L2 remains unclear. We studied malarial infections to understand the contribution of PD-L2 to immunity. Here we have shown that higher PD-L2 expression on blood dendritic cells, from Plasmodium falciparum-infected individuals, correlated with lower parasitemia. Mechanistic studies in mice showed that PD-L2 was indispensable for establishing effective CD4(+) T~cell immunity against malaria, because it not only inhibited PD-L1 to PD-1 activity but also increased CD3 and inducible co-stimulator (ICOS) expression on T~cells. Importantly, administration of soluble multimeric PD-L2 to mice with lethal malaria was sufficient to dramatically improve immunity and survival. These studies show immuno-regulation by PD-L2, which has the potential to be translated into an effective treatment for malaria and other diseases where T~cell immunity is ineffective or short-lived due to PD-1-mediated signaling.},
	issn = {1097-4180},
	doi = {10.1016/j.immuni.2016.07.017},
	author = {Karunarathne, Deshapriya S and Horne-Debets, Joshua M and Huang, Johnny X and Faleiro, Rebecca and Leow, Chiuan Yee and Amante, Fiona and Watkins, Thomas S and Miles, John J and Dwyer, Patrick J and Stacey, Katryn J and Yarski, Michael and Poh, Chek Meng and Lee, Jason S and Cooper, Matthew A and R{\'e}nia, Laurent and Richard, Derek and McCarthy, James S and Sharpe, Arlene H and Wykes, Michelle N}
}
@article {1051401,
	title = {Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy},
	journal = {Nature},
	volume = {537},
	number = {7620},
	year = {2016},
	month = {2016 09 15},
	pages = {417-421},
	abstract = {Chronic viral infections are characterized by a state of CD8(+) T-cell dysfunction that is associated with expression of the programmed cell death 1 (PD-1) inhibitory receptor. A better understanding of the mechanisms that regulate CD8(+) T-cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8(+) T cells. Here we identify a population of virus-specific CD8(+) T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These LCMV-specific CD8(+) T cells expressed the PD-1 inhibitory receptor, but also expressed several costimulatory molecules such as ICOS and CD28. This CD8(+) T-cell subset was characterized by a unique gene signature that was related to that of CD4(+) T follicular helper (TFH) cells, CD8(+) T cell memory precursors and haematopoietic stem cell progenitors, but that was distinct from that of CD4(+) TH1 cells and CD8(+) terminal effectors. This CD8(+) T-cell population was found only in lymphoid tissues and resided predominantly in the T-cell zones along with naive CD8(+) T cells. These PD-1(+)CD8(+) T cells resembled stem cells during chronic LCMV infection, undergoing self-renewal and also differentiating into the terminally exhausted CD8(+) T cells that were present in both lymphoid and non-lymphoid tissues. The proliferative burst after PD-1 blockade came almost exclusively from this CD8(+) T-cell subset. Notably, the transcription factor TCF1 had a cell-intrinsic and essential role in the generation of this CD8(+) T-cell subset. These findings provide a better understanding of T-cell exhaustion and have implications in the optimization of PD-1-directed immunotherapy in chronic infections and cancer.},
	keywords = {Animals, Antigens, CD28, CD8-Positive T-Lymphocytes, Cell Differentiation, Cell Proliferation, Cell Self Renewal, Female, Hematopoietic Stem Cells, Hepatocyte Nuclear Factor 1-alpha, Immunotherapy, Inducible T-Cell Co-Stimulator Protein, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Mice, Programmed Cell Death 1 Receptor, T-Lymphocyte Subsets, T-Lymphocytes, Helper-Inducer},
	issn = {1476-4687},
	doi = {10.1038/nature19330},
	author = {Im, Se Jin and Hashimoto, Masao and Gerner, Michael Y and Lee, Junghwa and Kissick, Haydn T and Burger, Matheus C and Shan, Qiang and Hale, J Scott and Lee, Judong and Nasti, Tahseen H and Sharpe, Arlene H and Freeman, Gordon J and Germain, Ronald N and Nakaya, Helder I and Xue, Hai-Hui and Ahmed, Rafi}
}
@article {1051371,
	title = {Type 2 innate lymphoid cell suppression by regulatory T~cells attenuates airway hyperreactivity and requires inducible T-cell costimulator-inducible T-cell costimulator ligand interaction},
	journal = {J Allergy Clin Immunol},
	year = {2016},
	month = {2016 Oct 04},
	abstract = {BACKGROUND: Atopic diseases, including asthma, exacerbate type 2 immune responses and involve a number of immune cell types, including regulatory T (Treg) cells and the emerging type 2 innate lymphoid cells (ILC2s). Although ILC2s are potent producers of type 2 cytokines, the regulation of ILC2 activation and function is not well understood.

OBJECTIVE: In the present study, for the first time, we evaluate how Treg cells interact with pulmonary ILC2s and control their function.

METHODS: ILC2s and Treg cells were evaluated by using in~vitro suppression assays, cell-contact assays, and gene expression panels. Also, human ILC2s and Treg cells were adoptively transferred into NOD SCID γC-deficient mice, which were given isotype or anti-inducible T-cell costimulator ligand (ICOSL) antibodies and then challenged with IL-33 and assessed for airway hyperreactivity.

RESULTS: We show that induced Treg cells, but not natural Treg cells, effectively suppress the production of the ILC2-driven proinflammatory cytokines IL-5 and IL-13 both in~vitro and in~vivo. Mechanistically, our data reveal the necessity of inducible T-cell costimulator (ICOS)-ICOS ligand cell contact for Treg cell-mediated ILC2 suppression alongside the suppressive cytokines TGF-β and IL-10. Using a translational approach, we then demonstrate that human induced Treg cells suppress syngeneic human ILC2s through ICOSL to control airway inflammation in a humanized ILC2 mouse model.

CONCLUSION: These findings suggest that peripheral expansion of induced Treg cells can serve as a promising therapeutic target against ILC2-dependent asthma.},
	issn = {1097-6825},
	doi = {10.1016/j.jaci.2016.08.034},
	author = {Rigas, Diamanda and Lewis, Gavin and Aron, Jennifer L and Wang, Bowen and Banie, Homayon and Sankaranarayanan, Ishwarya and Galle-Treger, Lauriane and Maazi, Hadi and Lo, Richard and Freeman, Gordon J and Sharpe, Arlene H and Soroosh, Pejman and Akbari, Omid}
}
@article {1051346,
	title = {Anti-CD48 Monoclonal Antibody Attenuates Experimental Autoimmune Encephalomyelitis by Limiting the Number of Pathogenic CD4+ T Cells},
	journal = {J Immunol},
	volume = {197},
	number = {8},
	year = {2016},
	month = {2016 Oct 15},
	pages = {3038-3048},
	abstract = {CD48 (SLAMF2) is an adhesion and costimulatory molecule constitutively expressed on hematopoietic cells. Polymorphisms in CD48 have been linked to susceptibility to multiple sclerosis (MS), and altered expression of the structurally related protein CD58 (LFA-3) is associated with disease remission in MS. We examined CD48 expression and function in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We found that a subpopulation of CD4(+) T cells highly upregulated CD48 expression during EAE and were enriched for pathogenic CD4(+) T cells. These CD48(++)CD4(+) T cells were predominantly CD44(+) and Ki67(+), included producers of IL-17A, GM-CSF, and IFN-γ, and were most of the CD4(+) T cells in the CNS. Administration of anti-CD48 mAb during EAE attenuated clinical disease, limited accumulation of lymphocytes in the CNS, and reduced the number of pathogenic cytokine-secreting CD4(+) T cells in the spleen at early time points. These therapeutic effects required CD48 expression on CD4(+) T cells but not on APCs. Additionally, the effects of anti-CD48 were partially dependent on FcγRs, as anti-CD48 did not ameliorate EAE or reduce the number of cytokine-producing effector CD4(+) T cells in Fcεr1γ(-/-) mice or in wild-type mice receiving anti-CD16/CD32 mAb. Our data suggest that anti-CD48 mAb exerts its therapeutic effects by both limiting CD4(+) T cell proliferation and preferentially eliminating pathogenic CD48(++)CD4(+) T cells during EAE. Our findings indicate that high CD48 expression is a feature of pathogenic CD4(+) T cells during EAE and point to CD48 as a potential target for immunotherapy.},
	issn = {1550-6606},
	doi = {10.4049/jimmunol.1600706},
	author = {McArdel, Shannon L and Brown, Daniel R and Sobel, Raymond A and Sharpe, Arlene H}
}
@article {1051321,
	title = {Suppression by TFR cells leads to durable and selective inhibition of B cell effector function},
	journal = {Nat Immunol},
	volume = {17},
	number = {12},
	year = {2016},
	month = {2016 Dec},
	pages = {1436-1446},
	abstract = {Follicular regulatory T cells (TFR cells) inhibit follicular helper T cell (TFH cell)-mediated antibody production. The mechanisms by which TFR cells exert their key immunoregulatory functions are largely unknown. Here we found that TFR cells induced a distinct suppressive state in TFH cells and B cells, in which effector transcriptional signatures were maintained but key effector molecules and metabolic pathways were suppressed. The suppression of B cell antibody production and metabolism by TFR cells was durable and persisted even in the absence of TFR cells. This durable suppression was due in part to epigenetic changes. The cytokine IL-21 was able to overcome TFR cell-mediated suppression and inhibited TFR cells and stimulated B cells. By determining mechanisms of TFR cell-mediated suppression, we have identified methods for modulating the function of TFR cells and antibody production.},
	issn = {1529-2916},
	doi = {10.1038/ni.3578},
	author = {Sage, Peter T and Ron-Harel, Noga and Juneja, Vikram R and Sen, Debattama R and Maleri, Seth and Sungnak, Waradon and Kuchroo, Vijay K and Haining, W Nicholas and Chevrier, Nicolas and Haigis, Marcia and Sharpe, Arlene H}
}
@article {1051201,
	title = {Binding of the cytoplasmic domain of CD28 to the plasma membrane inhibits Lck recruitment and signaling},
	journal = {Sci Signal},
	volume = {9},
	number = {438},
	year = {2016},
	month = {2016 Jul 26},
	pages = {ra75},
	abstract = {The T cell costimulatory receptor CD28 is required for the full activation of na{\"\i}ve T cells and for the development and maintenance of Foxp3(+) regulatory T (Treg) cells. We showed that the cytoplasmic domain of CD28 was bound to the plasma membrane in resting cells and that ligand binding to CD28 resulted in its release. Membrane binding by the CD28 cytoplasmic domain required two clusters of basic amino acid residues, which interacted with the negatively charged inner leaflet of the plasma membrane. These same clusters of basic residues also served as interaction sites for Lck, a Src family kinase critical for CD28 function. This signaling complex was further stabilized by the Lck-mediated phosphorylation of CD28 Tyr(207) and the subsequent binding of the Src homology 2 (SH2) domain of Lck to this phosphorylated tyrosine. Mutation of the basic clusters in the CD28 cytoplasmic domain reduced the recruitment to the CD28-Lck complex of protein kinase Cθ (PKCθ), which serves as a key effector kinase in the CD28 signaling pathway. Consequently, mutation of either a basic cluster or Tyr(207) impaired CD28 function in mice as shown by the reduced thymic differentiation of FoxP3(+) Treg cells. On the basis of these results, we propose a previously undescribed model for the initiation of CD28 signaling.},
	issn = {1937-9145},
	doi = {10.1126/scisignal.aaf0626},
	author = {Dobbins, Jessica and Gagnon, Etienne and Godec, Jernej and Pyrdol, Jason and Vignali, Dario A A and Sharpe, Arlene H and Wucherpfennig, Kai W}
}
@article {1051161,
	title = {Mitochondrial Biogenesis and Proteome Remodeling Promote One-Carbon Metabolism for T Cell Activation},
	journal = {Cell Metab},
	volume = {24},
	number = {1},
	year = {2016},
	month = {2016 Jul 12},
	pages = {104-17},
	abstract = {Naive T~cell stimulation activates anabolic metabolism to fuel the transition from quiescence to growth and proliferation. Here we show that naive CD4(+) T~cell activation induces a unique program of mitochondrial biogenesis and remodeling. Using mass spectrometry, we quantified protein dynamics during T~cell activation. We identified substantial remodeling of the mitochondrial proteome over the first 24~hr of T~cell activation to generate mitochondria with a distinct metabolic signature, with one-carbon metabolism as the most induced pathway. Salvage pathways and mitochondrial one-carbon metabolism, fed by serine, contribute to purine and thymidine synthesis to enable T~cell proliferation and survival. Genetic inhibition of the mitochondrial serine catabolic enzyme SHMT2 impaired T~cell survival in culture and antigen-specific T~cell abundance in~vivo. Thus, during T~cell activation, mitochondrial proteome remodeling generates specialized mitochondria with enhanced one-carbon metabolism that is critical for T~cell activation and survival.},
	issn = {1932-7420},
	doi = {10.1016/j.cmet.2016.06.007},
	author = {Ron-Harel, Noga and Santos, Daniel and Ghergurovich, Jonathan M and Sage, Peter T and Reddy, Anita and Lovitch, Scott B and Dephoure, Noah and Satterstrom, F Kyle and Sheffer, Michal and Spinelli, Jessica B and Gygi, Steven and Rabinowitz, Joshua D and Sharpe, Arlene H and Haigis, Marcia C}
}
@article {1051146,
	title = {Summary and Recommendations from the National Cancer Institute{\textquoteright}s Clinical Trials Planning Meeting on Novel Therapeutics for Non-Muscle Invasive Bladder Cancer},
	journal = {Bladder Cancer},
	volume = {2},
	number = {2},
	year = {2016},
	month = {2016 Apr 27},
	pages = {165-202},
	abstract = {The NCI Bladder Cancer Task Force convened a Clinical Trials Planning Meeting (CTPM) Workshop focused on Novel Therapeutics for Non-Muscle Invasive Bladder Cancer (NMIBC). Meeting attendees included a broad and multi-disciplinary group of clinical and research stakeholders and included leaders from NCI, FDA, National Clinical Trials Network (NCTN), advocacy and the pharmaceutical and biotech industry. The meeting goals and objectives were to: 1) create a collaborative environment in which the greater bladder research community can pursue future optimally designed novel clinical trials focused on the theme of molecular targeted and immune-based therapies in NMIBC; 2) frame the clinical and translational questions that are of highest priority; and 3) develop two clinical trial designs focusing on immunotherapy and molecular targeted therapy. Despite successful development and implementation of large Phase II and Phase III trials in bladder and upper urinary tract cancers, there are no active and accruing trials in the NMIBC space within the NCTN. Disappointingly, there has been only one new FDA approved drug (Valrubicin) in any bladder cancer disease state since 1998. Although genomic-based data for bladder cancer are increasingly available, translating these discoveries into practice changing treatment is still to come. Recently, major efforts in defining the genomic characteristics of NMIBC have been achieved. Aligned with these data is the growing number of targeted therapy agents approved and/or in development in other organ site cancers and the multiple similarities of bladder cancer with molecular subtypes in these other cancers. Additionally, although bladder cancer is one of the more immunogenic tumors, some tumors have the ability to attenuate or eliminate host immune responses. Two trial concepts emerged from the meeting including a window of opportunity trial (Phase 0) testing an FGFR3 inhibitor and a second multi-arm multi-stage trial testing combinations of BCG or radiotherapy and immunomodulatory agents in patients who recur after induction BCG (BCG failure).},
	issn = {2352-3727},
	doi = {10.3233/BLC-160053},
	author = {Lerner, Seth P and Bajorin, Dean F and Dinney, Colin P and Efstathiou, Jason A and Groshen, Susan and Hahn, Noah M and Hansel, Donna and Kwiatkowski, David and O{\textquoteright}Donnell, Michael and Rosenberg, Jonathan and Svatek, Robert and Abrams, Jeffrey S and Al-Ahmadie, Hikmat and Apolo, Andrea B and Bellmunt, Joaquim and Callahan, Margaret and Cha, Eugene K and Drake, Charles and Jarow, Jonathan and Kamat, Ashish and Kim, William and Knowles, Margaret and Mann, Bhupinder and Marchionni, Luigi and McConkey, David and McShane, Lisa and Ramirez, Nilsa and Sharabi, Andrew and Sharpe, Arlene H and Solit, David and Tangen, Catherine M and Amiri, Abdul Tawab and Van Allen, Eliezer and West, Pamela J and Witjes, J A and Quale, Diane Zipursky}
}
@article {1051121,
	title = {Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade},
	journal = {Cancer Discov},
	volume = {6},
	number = {8},
	year = {2016},
	month = {2016 Aug},
	pages = {827-37},
	abstract = {UNLABELLED: Immune checkpoint blockade represents a major breakthrough in cancer therapy; however, responses are not universal. Genomic and immune features in pretreatment tumor biopsies have been reported to correlate with response in patients with melanoma and other cancers, but robust biomarkers have not been identified. We studied a cohort of patients with metastatic melanoma initially treated with cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) blockade (n = 53) followed by programmed death-1 (PD-1) blockade at progression (n = 46), and analyzed immune signatures in longitudinal tissue samples collected at multiple time points during therapy. In this study, we demonstrate that adaptive immune signatures in tumor biopsy samples obtained early during the course of treatment are highly predictive of response to immune checkpoint blockade and also demonstrate differential effects on the tumor microenvironment induced by CTLA4 and PD-1 blockade. Importantly, potential mechanisms of therapeutic resistance to immune checkpoint blockade were also identified.

SIGNIFICANCE: These studies demonstrate that adaptive immune signatures in early on-treatment tumor biopsies are predictive of response to checkpoint blockade and yield insight into mechanisms of therapeutic resistance. These concepts have far-reaching implications in this age of precision medicine and should be explored in immune checkpoint blockade treatment across cancer types. Cancer Discov; 6(8); 827-37. {\textcopyright}2016 AACR.See related commentary by Teng et al., p. 818This article is highlighted in the In This Issue feature, p. 803.},
	issn = {2159-8290},
	doi = {10.1158/2159-8290.CD-15-1545},
	author = {Chen, Pei-Ling and Roh, Whijae and Reuben, Alexandre and Cooper, Zachary A and Spencer, Christine N and Prieto, Peter A and Miller, John P and Bassett, Roland L and Gopalakrishnan, Vancheswaran and Wani, Khalida and De Macedo, Mariana Petaccia and Austin-Breneman, Jacob L and Jiang, Hong and Chang, Qing and Reddy, Sangeetha M and Chen, Wei-Shen and Tetzlaff, Michael T and Broaddus, Russell J and Davies, Michael A and Gershenwald, Jeffrey E and Haydu, Lauren and Lazar, Alexander J and Patel, Sapna P and Hwu, Patrick and Hwu, Wen-Jen and Diab, Adi and Glitza, Isabella C and Woodman, Scott E and Vence, Luis M and Wistuba, Ignacio I and Amaria, Rodabe N and Kwong, Lawrence N and Prieto, Victor and Davis, R Eric and Ma, Wencai and Overwijk, Willem W and Sharpe, Arlene H and Hu, Jianhua and Futreal, P Andrew and Blando, Jorge and Sharma, Padmanee and Allison, James P and Chin, Lynda and Wargo, Jennifer A}
}
@article {1051061,
	title = {Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality},
	journal = {J Clin Invest},
	volume = {126},
	number = {7},
	year = {2016},
	month = {2016 Jul 01},
	pages = {2642-60},
	abstract = {Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD. In patients with severe GVHD, PD-L1 expression was increased on donor T cells. Compared with mice that received WT T cells, GVHD was reduced in animals that received T cells from Pdl1-/- donors. PD-L1-deficient T cells had reduced expression of gut homing receptors, diminished production of inflammatory cytokines, and enhanced rates of apoptosis. Moreover, multiple bioenergetic pathways, including aerobic glycolysis, oxidative phosphorylation, and fatty acid metabolism, were also reduced in T cells lacking PD-L1. Finally, the reduction of acute GVHD lethality in mice that received Pdl1-/- donor cells did not affect graft-versus-leukemia responses. These data demonstrate that PD-L1 selectively enhances T cell-mediated immune responses, suggesting a context-dependent function of the PD-1/PD-L1 axis, and suggest selective inhibition of PD-L1 on donor T cells as a potential strategy to prevent or ameliorate GVHD.},
	issn = {1558-8238},
	doi = {10.1172/JCI85796},
	author = {Saha, Asim and O{\textquoteright}Connor, Roddy S and Thangavelu, Govindarajan and Lovitch, Scott B and Dandamudi, Durga Bhavani and Wilson, Caleph B and Vincent, Benjamin G and Tkachev, Victor and Pawlicki, Jan M and Furlan, Scott N and Kean, Leslie S and Aoyama, Kazutoshi and Taylor, Patricia A and Panoskaltsis-Mortari, Angela and Foncea, Rocio and Ranganathan, Parvathi and Devine, Steven M and Burrill, Joel S and Guo, Lili and Sacristan, Catarina and Snyder, Nathaniel W and Blair, Ian A and Milone, Michael C and Dustin, Michael L and Riley, James L and Bernlohr, David A and Murphy, William J and Fife, Brian T and Munn, David H and Miller, Jeffrey S and Serody, Jonathan S and Freeman, Gordon J and Sharpe, Arlene H and Turka, Laurence A and Blazar, Bruce R}
}
@article {1051016,
	title = {CD4 T Cell-Derived IFN-γ Plays a Minimal Role in Control of Pulmonary Mycobacterium tuberculosis Infection and Must Be Actively Repressed by PD-1 to Prevent Lethal Disease},
	journal = {PLoS Pathog},
	volume = {12},
	number = {5},
	year = {2016},
	month = {2016 May},
	pages = {e1005667},
	abstract = {IFN-γ-producing CD4 T cells are required for protection against Mycobacterium tuberculosis (Mtb) infection, but the extent to which IFN-γ contributes to overall CD4 T cell-mediated protection remains unclear. Furthermore, it is not known if increasing IFN-γ production by CD4 T cells is desirable in Mtb infection. Here we show that IFN-γ accounts for only ~30\% of CD4 T cell-dependent cumulative bacterial control in the lungs over the first six weeks of infection, but >80\% of control in the spleen. Moreover, increasing the IFN-γ-producing capacity of CD4 T cells by ~2 fold exacerbates lung infection and leads to the early death of the host, despite enhancing control in the spleen. In addition, we show that the inhibitory receptor PD-1 facilitates host resistance to Mtb by preventing the detrimental over-production of IFN-γ by CD4 T cells. Specifically, PD-1 suppressed the parenchymal accumulation of and pathogenic IFN-γ production by the CXCR3+KLRG1-CX3CR1- subset of lung-homing CD4 T cells that otherwise mediates control of Mtb infection. Therefore, the primary role for T cell-derived IFN-γ in Mtb infection is at extra-pulmonary sites, and the host-protective subset of CD4 T cells requires negative regulation of IFN-γ production by PD-1 to prevent lethal immune-mediated pathology.},
	issn = {1553-7374},
	doi = {10.1371/journal.ppat.1005667},
	author = {Sakai, Shunsuke and Kauffman, Keith D and Sallin, Michelle A and Sharpe, Arlene H and Young, Howard A and Ganusov, Vitaly V and Barber, Daniel L}
}
@article {1050981,
	title = {Coinhibitory Pathways in the B7-CD28 Ligand-Receptor Family},
	journal = {Immunity},
	volume = {44},
	number = {5},
	year = {2016},
	month = {2016 May 17},
	pages = {955-72},
	abstract = {Immune responses need to be controlled for optimal protective immunity and tolerance. Coinhibitory pathways in the B7-CD28 family provide critical inhibitory signals that regulate immune homeostasis and defense and protect tissue integrity. These coinhibitory signals limit the strength and duration of immune responses, thereby curbing immune-mediated tissue damage, regulating resolution of inflammation, and maintaining tolerance to prevent autoimmunity. Tumors and microbes that cause chronic infections can exploit these coinhibitory pathways to establish an immunosuppressive microenvironment, hindering their eradication. Advances in understanding T~cell coinhibitory pathways have stimulated a new era of immunotherapy with effective drugs to treat cancer, autoimmune and infectious diseases, and transplant rejection. In this review we discuss the current knowledge of the mechanisms underlying the coinhibitory functions of pathways in the B7-CD28 family, the diverse functional consequences of these inhibitory signals on immune responses, and the overlapping and unique functions of these key immunoregulatory pathways.},
	issn = {1097-4180},
	doi = {10.1016/j.immuni.2016.05.002},
	author = {Schildberg, Frank A and Klein, Sarah R and Freeman, Gordon J and Sharpe, Arlene H}
}
@article {702896,
	title = {Coinhibitory Pathways in Immunotherapy for Cancer.},
	journal = {Annu Rev Immunol},
	volume = {34},
	year = {2016},
	month = {2016 May 20},
	pages = {539-73},
	abstract = {The immune system is capable of recognizing tumors and eliminates many early malignant cells. However, tumors evolve to evade immune attack, and the tumor microenvironment is immunosuppressive. Immune responses are regulated by a number of immunological checkpoints that promote protective immunity and maintain tolerance. T cell coinhibitory pathways restrict the strength and duration of immune responses, thereby limiting immune-mediated tissue damage, controlling resolution of inflammation, and maintaining tolerance to prevent autoimmunity. Tumors exploit these coinhibitory pathways to evade immune eradication. Blockade of the PD-1 and CTLA-4 checkpoints is proving to be an effective and durable cancer immunotherapy in a subset of patients with a variety of tumor types, and additional combinations are further improving response rates. In this review we discuss the immunoregulatory functions of coinhibitory pathways and their translation to effective immunotherapies for cancer.},
	issn = {1545-3278},
	doi = {10.1146/annurev-immunol-032414-112049},
	author = {Baumeister, Susanne H and Freeman, Gordon J and Dranoff, Glenn and Sharpe, Arlene H}
}
@article {702886,
	title = {Distinct clinical patterns and immune infiltrates are observed at time of progression on targeted therapy versus immune checkpoint blockade for melanoma.},
	journal = {Oncoimmunology},
	volume = {5},
	number = {3},
	year = {2016},
	month = {2016 Mar},
	pages = {e1136044},
	abstract = {We have made major advances in the treatment of melanoma through the use of targeted therapy and immune checkpoint blockade; however, clinicians are posed with therapeutic dilemmas regarding timing and sequence of therapy. There is a growing appreciation of the impact of antitumor immune responses to these therapies, and we performed studies to test the hypothesis that clinical patterns and immune infiltrates differ at progression on these treatments. We observed rapid clinical progression kinetics in patients on targeted therapy compared to immune checkpoint blockade. To gain insight into possible immune mechanisms behind these differences, we performed deep immune profiling in tumors of patients on therapy. We demonstrated low CD8(+) T-cell infiltrate on targeted therapy and high CD8(+) T-cell infiltrate on immune checkpoint blockade at clinical progression. These data have important implications, and suggest that antitumor immune responses should be assessed when considering therapeutic options for patients with melanoma.},
	issn = {2162-4011},
	doi = {10.1080/2162402X.2015.1136044},
	author = {Cooper, Zachary A and Reuben, Alexandre and Spencer, Christine N and Prieto, Peter A and Austin-Breneman, Jacob L and Jiang, Hong and Haymaker, Cara and Gopalakrishnan, Vancheswaran and Tetzlaff, Michael T and Frederick, Dennie T and Sullivan, Ryan J and Amaria, Rodabe N and Patel, Sapna P and Hwu, Patrick and Woodman, Scott E and Glitza, Isabella C and Diab, Adi and Vence, Luis M and Rodriguez-Canales, Jaime and Parra, Edwin R and Wistuba, Ignacio I and Coussens, Lisa M and Sharpe, Arlene H and Flaherty, Keith T and Gershenwald, Jeffrey E and Chin, Lynda and Davies, Michael A and Clise-Dwyer, Karen and Allison, James P and Sharma, Padmanee and Wargo, Jennifer A}
}
@article {702911,
	title = {Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model.},
	journal = {Cancer Immunol Res},
	volume = {4},
	number = {2},
	year = {2016},
	month = {2016 Feb},
	pages = {124-35},
	abstract = {Inhibition of immune checkpoints, including cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and its ligand PD-L1, has demonstrated exciting and durable remissions across a spectrum of malignancies. Combinatorial regimens blocking complementary immune checkpoints further enhance the therapeutic benefit. The activity of these agents for patients with glioblastoma, a generally lethal primary brain tumor associated with significant systemic and microenvironmental immunosuppression, is not known. We therefore systematically evaluated the antitumor efficacy of murine antibodies targeting a broad panel of immune checkpoint molecules, including CTLA-4, PD-1, PD-L1, and PD-L2 when administered as single-agent therapy and in combinatorial regimens against an orthotopic, immunocompetent murine glioblastoma model. In these experiments, we observed long-term tumor-free survival following single-agent anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy in 50\%, 20\%, and 15\% of treated animals, respectively. Combination therapy of anti-CTLA-4 plus anti-PD-1 cured 75\% of the animals, even against advanced, later-stage tumors. In long-term survivors, tumor growth was not seen upon intracranial tumor rechallenge, suggesting that tumor-specific immune memory responses were generated. Inhibitory immune checkpoint blockade quantitatively increased activated CD8(+) and natural killer cells and decreased suppressive immune cells in the tumor microenvironment and draining cervical lymph nodes. Our results support prioritizing the clinical evaluation of PD-1, PD-L1, and CTLA-4 single-agent targeted therapy as well as combination therapy of CTLA-4 plus PD-1 blockade for patients with glioblastoma. Cancer Immunol Res; 4(2); 124-35. {\textcopyright}2015 AACR.},
	issn = {2326-6074},
	doi = {10.1158/2326-6066.CIR-15-0151},
	author = {Reardon, David A and Gokhale, Prafulla C and Klein, Sarah R and Ligon, Keith L and Rodig, Scott J and Ramkissoon, Shakti H and Jones, Kristen L and Conway, Amy Saur and Liao, Xiaoyun and Zhou, Jun and Wen, Patrick Y and Van Den Abbeele, Annick D and Hodi, F Stephen and Qin, Lei and Kohl, Nancy E and Sharpe, Arlene H and Dranoff, Glenn and Freeman, Gordon J}
}
@article {702901,
	title = {Roles of CD48 in regulating immunity and tolerance.},
	journal = {Clin Immunol},
	volume = {164},
	year = {2016},
	month = {2016 Mar},
	pages = {10-20},
	abstract = {CD48, a member of the signaling lymphocyte activation molecule family, participates in adhesion and activation of immune cells. Although constitutively expressed on most hematopoietic cells, CD48 is upregulated on subsets of activated cells. CD48 can have activating roles on T cells, antigen presenting cells and granulocytes, by binding to CD2 or bacterial FimH, and through cell intrinsic effects. Interactions between CD48 and its high affinity ligand CD244 are more complex, with both stimulatory and inhibitory outcomes. CD244:CD48 interactions regulate target cell lysis by NK cells and CTLs, which are important for viral clearance and regulation of effector/memory T cell generation and survival. Here we review roles of CD48 in infection, tolerance, autoimmunity, and allergy, as well as the tools used to investigate this receptor. We discuss stimulatory and regulatory roles for CD48, its potential as a therapeutic target in human disease, and current challenges to investigation of this immunoregulatory receptor.},
	issn = {1521-7035},
	doi = {10.1016/j.clim.2016.01.008},
	author = {McArdel, Shannon L and Terhorst, Cox and Sharpe, Arlene H}
}
@article {702891,
	title = {T follicular regulatory cells.},
	journal = {Immunol Rev},
	volume = {271},
	number = {1},
	year = {2016},
	month = {2016 May},
	pages = {246-59},
	abstract = {Pathogen exposure elicits production of high-affinity antibodies stimulated by T follicular helper (Tfh) cells in the germinal center reaction. Tfh cells provide both costimulation and stimulatory cytokines to B cells to facilitate affinity maturation, class switch recombination, and plasma cell differentiation within the germinal center. Under normal circumstances, the germinal center reaction results in antibodies that precisely target foreign pathogens while limiting autoimmunity and excessive inflammation. In order to have this degree of control, the immune system ensures Tfh-mediated B-cell help is regulated locally in the germinal center. The recently identified T follicular regulatory (Tfr) cell subset can migrate to the germinal center and inhibit Tfh-mediated B-cell activation and antibody production. Although many aspects of Tfr cell biology are still unclear, recent data have begun to delineate the specialized roles of Tfr cells in controlling the germinal center reaction. Here we discuss the current understanding of Tfr-cell differentiation and function and how this knowledge is providing new insights into the dynamic regulation of germinal centers, and suggesting more efficacious vaccine strategies and ways to treat antibody-mediated diseases.},
	issn = {1600-065X},
	doi = {10.1111/imr.12411},
	author = {Sage, Peter T and Sharpe, Arlene H}
}
@article {702921,
	title = {CD39 Expression Identifies Terminally Exhausted CD8+ T Cells.},
	journal = {PLoS Pathog},
	volume = {11},
	number = {10},
	year = {2015},
	month = {2015 Oct},
	pages = {e1005177},
	abstract = {Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion.},
	keywords = {Animals, Antigens, CD, Apyrase, Arenaviridae Infections, Biomarkers, CD8-Positive T-Lymphocytes, Chromatography, High Pressure Liquid, Chronic Disease, Disease Models, Animal, Flow Cytometry, Hepatitis C, Chronic, HIV Infections, Humans, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Mice, Mice, Inbred C57BL, Oligonucleotide Array Sequence Analysis, RNA Virus Infections, T-Lymphocyte Subsets},
	issn = {1553-7374},
	doi = {10.1371/journal.ppat.1005177},
	author = {Gupta, Prakash K and Godec, Jernej and Wolski, David and Adland, Emily and Yates, Kathleen and Pauken, Kristen E and Cosgrove, Cormac and Ledderose, Carola and Junger, Wolfgang G and Robson, Simon C and Wherry, E John and Alter, Galit and Goulder, Philip J R and Klenerman, Paul and Sharpe, Arlene H and Lauer, Georg M and Haining, W Nicholas}
}
@article {702916,
	title = {PD-L1 Antibodies to Its Cytoplasmic Domain Most Clearly Delineate Cell Membranes in Immunohistochemical Staining of Tumor Cells.},
	journal = {Cancer Immunol Res},
	volume = {3},
	number = {12},
	year = {2015},
	month = {2015 Dec},
	pages = {1308-15},
	abstract = {Blocking the programmed death-1 (PD-1) pathway has clinical benefit in metastatic cancer and has led to the approval of the mAbs pembrolizumab and nivolumab to treat melanoma and nivolumab for non-small cell lung cancer. Expression of PD-L1 on the cell surface of either tumor cells or infiltrating immune cells is associated with a higher likelihood of response to PD-1 blockade in multiple studies. Most mAbs to PD-L1 in use are directed to its extracellular domain and immunohistochemically stain tumor tissue with a mixture of cytoplasmic and membrane staining. Cytoplasmic staining obscures the interpretation of a positive reaction on the tumor cell membrane, and thus affects the accuracy of PD-L1 scoring systems. We developed a mAb to the cytoplasmic domain of PD-L1, 405.9A11 (9A11), which is both more selective for membranous PD-L1 and more sensitive in IHC and Western blotting, compared with previous mAbs specific for the PD-L1 extracellular domain. Here, we compare immunohistochemical staining patterns of PD-L1 expression in five types of tumors, using five PD-L1 mAbs: 9A11, 7G11, and three commercially available mAbs. We demonstrate that 9A11, as well as two other cytoplasmic domain-specific mAbs, E1L3N and SP142, can clearly delineate the membrane of PD-L1-positive cells in formalin-fixed paraffin-embedded tissue and facilitate interpretation of staining results.},
	issn = {2326-6074},
	doi = {10.1158/2326-6066.CIR-15-0116},
	author = {Mahoney, Kathleen M and Sun, Heather and Liao, Xiaoyun and Hua, Ping and Callea, Marcella and Greenfield, Edward A and Hodi, F Stephen and Sharpe, Arlene H and Signoretti, Sabina and Rodig, Scott J and Freeman, Gordon J}
}
@article {702906,
	title = {The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment.},
	journal = {Sci Adv},
	volume = {1},
	number = {10},
	year = {2015},
	month = {2015 Nov},
	pages = {e1500845},
	abstract = {The tumor microenvironment is profoundly immunosuppressive. We show that multiple tumor types create intratumoral immune suppression driven by a specialized form of regulatory T cell (Treg) activation dependent on the PTEN (phosphatase and tensin homolog) lipid phosphatase. PTEN acted to stabilize Tregs in tumors, preventing them from reprogramming into inflammatory effector cells. In mice with a Treg-specific deletion of PTEN, tumors grew slowly, were inflamed, and could not create an immunosuppressive tumor microenvironment. In normal mice, exposure to apoptotic tumor cells rapidly elicited PTEN-expressing Tregs, and PTEN-deficient mice were unable to maintain tolerance to apoptotic cells. In wild-type mice with large established tumors, pharmacologic inhibition of PTEN after chemotherapy or immunotherapy profoundly reconfigured the tumor microenvironment, changing it from a suppressive to an inflammatory milieu, and tumors underwent rapid regression. Thus, the immunosuppressive milieu in tumors must be actively maintained, and tumors become susceptible to immune attack if the PTEN pathway in Tregs is disrupted.},
	issn = {2375-2548},
	doi = {10.1126/sciadv.1500845},
	author = {Sharma, Madhav D and Shinde, Rahul and McGaha, Tracy L and Huang, Lei and Holmgaard, Rikke B and Wolchok, Jedd D and Mautino, Mario R and Celis, Esteban and Sharpe, Arlene H and Francisco, Loise M and Powell, Jonathan D and Yagita, Hideo and Mellor, Andrew L and Blazar, Bruce R and Munn, David H}
}
@article {549076,
	title = {Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells.},
	journal = {J Exp Med},
	volume = {212},
	number = {7},
	year = {2015},
	month = {2015 Jun 29},
	pages = {1125-37},
	abstract = {Programmed Death-1 (PD-1) has received considerable attention as a key regulator of CD8(+) T cell exhaustion during chronic infection and cancer because blockade of this pathway partially reverses T cell dysfunction. Although the PD-1 pathway is critical in regulating established "exhausted" CD8(+) T cells (TEX cells), it is unclear whether PD-1 directly causes T cell exhaustion. We show that PD-1 is not required for the induction of exhaustion in mice with chronic lymphocytic choriomeningitis virus (LCMV) infection. In fact, some aspects of exhaustion are more severe with genetic deletion of PD-1 from the onset of infection. Increased proliferation between days 8 and 14 postinfection is associated with subsequent decreased CD8(+) T cell survival and disruption of a critical proliferative hierarchy necessary to maintain exhausted populations long term. Ultimately, the absence of PD-1 leads to the accumulation of more cytotoxic, but terminally differentiated, CD8(+) TEX cells. These results demonstrate that CD8(+) T cell exhaustion can occur in the absence of PD-1. They also highlight a novel role for PD-1 in preserving TEX cell populations from overstimulation, excessive proliferation, and terminal differentiation.},
	keywords = {Adoptive Transfer, Animals, Bromodeoxyuridine, CD8-Positive T-Lymphocytes, Cell Differentiation, Cell Proliferation, Flow Cytometry, Lymphocytic Choriomeningitis, Mice, Programmed Cell Death 1 Receptor},
	issn = {1540-9538},
	doi = {10.1084/jem.20142237},
	author = {Odorizzi, Pamela M and Pauken, Kristen E and Paley, Michael A and Sharpe, Arlene and Wherry, E John}
}
@article {542026,
	title = {Hepatic immune regulation by stromal cells.},
	journal = {Curr Opin Immunol},
	volume = {32},
	year = {2015},
	month = {2015 Feb},
	pages = {1-6},
	abstract = {A metabolic organ, the liver also has a central role in tolerance induction. Stromal cells lining the hepatic sinusoids, such as liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), are the first liver cells to encounter gut-derived and systemic antigens, thereby shaping local and systemic tolerance. Recent studies have demonstrated that stromal cells can modulate immune responses by antigen-dependent and independent mechanisms. Stromal cells interfere with the function of other antigen-presenting cells (APCs) and induce non-responsive T cells as well as regulatory T cells and myeloid-derived suppressor cells (MDSCs). The immunosuppressive microenvironment thus created provides a means to protect the liver from tissue damage. Such tolerized surroundings, however, can be exploited by certain pathogens, promoting persistent liver infections.},
	issn = {1879-0372},
	doi = {10.1016/j.coi.2014.10.002},
	author = {Schildberg, Frank A and Sharpe, Arlene H and Turley, Shannon J}
}
@article {542011,
	title = {Inducible RNAi in vivo reveals that the transcription factor BATF is required to initiate but not maintain CD8+ T-cell effector differentiation.},
	journal = {Proc Natl Acad Sci U S A},
	volume = {112},
	number = {2},
	year = {2015},
	month = {2015 Jan 13},
	pages = {512-7},
	abstract = {The differentiation of effector CD8(+) T cells is critical for the development of protective responses to pathogens and for effective vaccines. In the first few hours after activation, naive CD8(+) T cells initiate a transcriptional program that leads to the formation of effector and memory T cells, but the regulation of this process is poorly understood. Investigating the role of specific transcription factors (TFs) in determining CD8(+) effector T-cell fate by gene knockdown with RNAi is challenging because naive T cells are refractory to transduction with viral vectors without extensive ex vivo stimulation, which obscures the earliest events in effector differentiation. To overcome this obstacle, we developed a novel strategy to test the function of genes in naive CD8(+) T cells in vivo by creating bone marrow chimera from hematopoietic progenitors transduced with an inducible shRNA construct. Following hematopoietic reconstitution, this approach allowed inducible in vivo gene knockdown in any cell type that developed from this transduced progenitor pool. We demonstrated that lentivirus-transduced progenitor cells could reconstitute normal hematopoiesis and develop into naive CD8(+) T cells that were indistinguishable from wild-type naive T cells. This experimental system enabled induction of efficient gene knockdown in vivo without subsequent manipulation. We applied this strategy to show that the TF BATF is essential for initial commitment of naive CD8(+) T cells to effector development but becomes dispensable by 72h. This approach makes possible the study of gene function in vivo in unperturbed cells of hematopoietic origin that are refractory to viral transduction.},
	keywords = {Animals, Basic-Leucine Zipper Transcription Factors, CD8-Positive T-Lymphocytes, Cell Differentiation, Gene Knockdown Techniques, Hematopoietic Stem Cells, Lentivirus, Mice, Mice, Inbred C57BL, Mice, Transgenic, RNA Interference, RNA, Small Interfering, Transduction, Genetic, Transplantation Chimera},
	issn = {1091-6490},
	doi = {10.1073/pnas.1413291112},
	author = {Godec, Jernej and Cowley, Glenn S and Barnitz, R Anthony and Root, David E and Sharpe, Arlene H and Haining, W Nicholas}
}
@article {542041,
	title = {Mitochondrial metabolism in T cell activation and senescence: a mini-review.},
	journal = {Gerontology},
	volume = {61},
	number = {2},
	year = {2015},
	month = {2015},
	pages = {131-8},
	abstract = {The aging immune system is unable to optimally respond to pathogens and generate long-term immunological memory against encountered antigens. Amongst the immune components most affected by aging are T lymphocytes. T lymphocytes are cells of the cell-mediated immune system, which can recognize microbial antigens and either directly kill infected cells or support the maturation and activation of other immune cells. When activated, T cells undergo a metabolic switch to accommodate their changing needs at every stage of the immune response. Here we review the different aspects of metabolic regulation of T cell activation, focusing on the emerging role of mitochondrial metabolism, and discuss changes that may contribute to age-related decline in T cell potency. Better understanding of the role of mitochondrial metabolism in immune cell function could provide insights into mechanisms of immune senescence with the potential for developing novel therapeutic approaches to improve immune responses in aged individuals.},
	issn = {1423-0003},
	doi = {10.1159/000362502},
	author = {Ron-Harel, Noga and Sharpe, Arlene H and Haigis, Marcia C}
}
@article {542031,
	title = {Ox40L-Ox40 pathway plays distinct roles in regulating Th2 responses but does not determine outcome of cutaneous leishmaniasis caused by Leishmania mexicana and Leishmania major.},
	journal = {Exp Parasitol},
	volume = {148},
	year = {2015},
	month = {2015 Jan},
	pages = {49-55},
	abstract = {Ox40 ligand (Ox40L)-Ox40 pathway has been shown to enhance Th2 responses and play a role in pathogenesis of cutaneous leishmaniasis (CL) caused by Leishmania major. Using Ox40l(-/-) BALB/c mice we analyzed the role of this pathway in determining the outcome to CL caused by L.~mexicana and compared to L.~major. Contrary to our expectations, Ox40l(-/-) mice were highly susceptible to both L.~major (LV39) and L.~mexicana (M379) and developed large non-healing lesions containing parasites comparable to Ox40l(+/+) BALB/c mice. Interestingly, upon in vitro stimulation with Leishmania antigen (LmAg), the lymph node cells from L.~major infected Ox40l(-/-) mice produced significantly less IL-4 and IL-10 compared to Ox40l(+/+) mice. L.~mexicana infected Ox40l(-/-) and Ox40l(+/+) mice did not show any difference in the production of IL-4 and IL-10. No difference was noted in the amount of Th1 cytokines IFN-ү and IL-12 produced by Ox40l(-/-) and Ox40l(+/+) mice infected with either parasite. These results indicate that the Ox40L-Ox40 pathway promotes Th2 bias only in L.~major infection but not L.~mexicana infection and this pathway is not critical for susceptibility to CL.},
	keywords = {Animals, Antibodies, Protozoan, Cytokines, Female, Leishmania major, Leishmania mexicana, Leishmaniasis, Cutaneous, Mice, Mice, Inbred BALB C, OX40 Ligand, Receptors, OX40, Th2 Cells, Virulence},
	issn = {1090-2449},
	doi = {10.1016/j.exppara.2014.11.002},
	author = {Tuladhar, Rashmi and Oghumu, Steve and Dong, Ran and Peterson, Allison and Sharpe, Arlene H and Satoskar, Abhay R}
}
@article {541971,
	title = {ABCB5 Identifies Immunoregulatory Dermal Cells.},
	journal = {Cell Rep},
	volume = {12},
	number = {10},
	year = {2015},
	month = {2015 Sep 8},
	pages = {1564-74},
	abstract = {Cell-based strategies represent a new frontier in the treatment of immune-mediated disorders. However, the paucity of markers for isolation of molecularly defined immunomodulatory cell populations poses a barrier to this field. Here, we show that ATP-binding~cassette member B5 (ABCB5) identifies dermal immunoregulatory cells (DIRCs) capable of exerting therapeutic immunoregulatory functions through engagement of programmed cell death 1 (PD-1). Purified Abcb5(+) DIRCs suppressed T~cell proliferation, evaded immune rejection, homed to recipient immune tissues, and induced Tregs in~vivo. In fully major-histocompatibility-complex-mismatched cardiac allotransplantation models, allogeneic DIRCs significantly prolonged allograft survival. Blockade of DIRC-expressed PD-1 reversed the inhibitory effects of DIRCs on T~cell activation, inhibited DIRC-dependent Treg induction, and attenuated DIRC-induced prolongation of cardiac allograft survival, indicating that DIRC immunoregulatory function is mediated, at least in part, through PD-1. Our results identify ABCB5(+) DIRCs as a distinct immunoregulatory cell population and suggest promising roles of this expandable cell subset in cellular immunotherapy.},
	issn = {2211-1247},
	doi = {10.1016/j.celrep.2015.08.010},
	author = {Schatton, Tobias and Yang, Jun and Kleffel, Sonja and Uehara, Mayuko and Barthel, Steven R and Schlapbach, Christoph and Zhan, Qian and Dudeney, Stephen and Mueller, Hansgeorg and Lee, Nayoung and de Vries, Juliane C and Meier, Barbara and Vander Beken, Seppe and Kluth, Mark A and Ganss, Christoph and Sharpe, Arlene H and Waaga-Gasser, Ana Maria and Sayegh, Mohamed H and Abdi, Reza and Scharffetter-Kochanek, Karin and Murphy, George F and Kupper, Thomas S and Frank, Natasha Y and Frank, Markus H}
}
@article {542006,
	title = {Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability.},
	journal = {Nat Immunol},
	volume = {16},
	number = {2},
	year = {2015},
	month = {2015 Feb},
	pages = {188-96},
	abstract = {Foxp3(+) regulatory T cells (Treg cells) are required for immunological homeostasis. One notable distinction between conventional T cells (Tconv cells) and Treg cells is differences in the activity of phosphatidylinositol-3-OH kinase (PI(3)K); only Tconv cells downregulate PTEN, the main negative regulator of PI(3)K, upon activation. Here we found that control of PI(3)K in Treg cells was essential for lineage homeostasis and stability. Mice lacking Pten in Treg cells developed an autoimmune-lymphoproliferative disease characterized by excessive T helper type 1 (TH1) responses and B cell activation. Diminished control of PI(3)K activity in Treg cells led to reduced expression of the interleukin-2 (IL-2) receptor α subunit CD25, accumulation of Foxp3(+)CD25(-) cells and, ultimately, loss of expression of the transcription factor Foxp3 in these cells. Collectively, our data demonstrate that control of PI(3)K signaling by PTEN in Treg cells is critical for maintaining their homeostasis, function and stability.},
	keywords = {Animals, Cell Lineage, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Gene Deletion, Homeostasis, Mice, Phosphatidylinositol 3-Kinases, PTEN Phosphohydrolase, Signal Transduction, T-Lymphocytes, Regulatory},
	issn = {1529-2916},
	doi = {10.1038/ni.3077},
	author = {Huynh, Alexandria and DuPage, Michel and Priyadharshini, Bhavana and Sage, Peter T and Quiros, Jason and Borges, Christopher M and Townamchai, Natavudh and Gerriets, Valerie A and Rathmell, Jeffrey C and Sharpe, Arlene H and Bluestone, Jeffrey A and Turka, Laurence A}
}
@article {541976,
	title = {Defective TFH Cell Function and Increased TFR Cells Contribute to Defective Antibody Production in Aging.},
	journal = {Cell Rep},
	volume = {12},
	number = {2},
	year = {2015},
	month = {2015 Jul 14},
	pages = {163-71},
	abstract = {Defective antibody production in aging is broadly attributed to immunosenescence. However, the precise immunological mechanisms remain unclear. Here, we demonstrate an increase in the ratio of inhibitory T follicular regulatory (TFR) cells to stimulatory T follicular helper (TFH) cells in aged mice. Aged TFH and TFR cells are phenotypically distinct from those in young mice, exhibiting increased programmed cell death protein-1 expression but decreased ICOS expression. Aged TFH cells exhibit defective antigen-specific responses, and programmed cell death protein-ligand 1 blockade can partially rescue TFH cell function. In contrast, young and aged TFR cells have similar suppressive capacity on a per-cell basis in vitro and in vivo. Together, these studies reveal mechanisms contributing to defective humoral immunity in aging: an increase in suppressive TFR cells combined with impaired function of aged TFH cells results in reduced T-cell-dependent antibody responses in aged mice.},
	issn = {2211-1247},
	doi = {10.1016/j.celrep.2015.06.015},
	author = {Sage, Peter T and Tan, Catherine L and Freeman, Gordon J and Haigis, Marcia and Sharpe, Arlene H}
}
@article {541961,
	title = {Deletion of CTLA-4 on regulatory T cells during adulthood leads to resistance to autoimmunity.},
	journal = {J Exp Med},
	year = {2015},
	month = {2015 Sep 14},
	abstract = {Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of T cell responses. Germline Ctla4 deficiency is lethal, making investigation of the function of CTLA-4 on mature T cells challenging. To elucidate the function of CTLA-4 on mature T cells, we have conditionally ablated Ctla4 in adult mice. We show that, in contrast to germline knockout mice, deletion of Ctla4 during adulthood does not precipitate systemic autoimmunity, but surprisingly confers protection from experimental autoimmune encephalomyelitis (EAE) and does not lead to increased resistance to MC38 tumors. Deletion of Ctla4 during adulthood was accompanied by activation and expansion of both conventional CD4(+)Foxp3(-) (T conv) and regulatory Foxp3(+) (T reg cells) T cell subsets; however, deletion of CTLA-4 on T reg cells was necessary and sufficient for protection from EAE. CTLA-4 deleted T reg cells remained functionally suppressive. Deletion of Ctla4 on T reg cells alone or on all adult T cells led to major changes in the Ctla4 sufficient T conv cell compartment, including up-regulation of immunoinhibitory molecules IL-10, LAG-3 and PD-1, thereby providing a compensatory immunosuppressive mechanism. Collectively, our findings point to a profound role for CTLA-4 on T reg cells in limiting their peripheral expansion and activation, thereby regulating the phenotype and function of T conv cells.},
	issn = {1540-9538},
	doi = {10.1084/jem.20141030},
	author = {Paterson, Alison M and Lovitch, Scott B and Sage, Peter T and Juneja, Vikram R and Lee, Youjin and Trombley, Justin D and Arancibia-C{\'a}rcamo, Carolina V and Sobel, Raymond A and Rudensky, Alexander Y and Kuchroo, Vijay K and Freeman, Gordon J and Sharpe, Arlene H}
}
@article {541996,
	title = {Helicobacter pylori cag pathogenicity island{\textquoteright}s role in B7-H1 induction and immune evasion.},
	journal = {PLoS One},
	volume = {10},
	number = {3},
	year = {2015},
	month = {2015},
	pages = {e0121841},
	abstract = {During Helicobacter pylori (H. pylori) infection CD4+ T cells in the gastric lamina propria are hyporesponsive and polarized by Th1/Th17 cell responses controlled by Treg cells. We have previously shown that H. pylori upregulates B7-H1 expression on GEC, which, in turn, suppress T cell proliferation, effector function, and induce Treg cells in vitro. In this study, we investigated the underlying mechanisms and the functional relevance of B7-H1 induction by H. pylori infection to chronic infection. Using H. pylori wild type (WT), cag pathogenicity island (cag PAI-) and cagA- isogenic mutant strains we demonstrated that H. pylori requires its type 4 secretion system (T4SS) as well as its effector protein CagA and peptidoglycan (PG) fragments for B7-H1 upregulation on GEC. Our study also showed that H. pylori uses the p38 MAPK pathway to upregulate B7-H1 expression in GEC. In vivo confirmation was obtained when infection of C57BL/6 mice with H. pylori PMSS1 strain, which has a functional T4SS delivery system, but not with H. pylori SS1 strain lacking a functional T4SS, led to a strong upregulation of B7-H1 expression in the gastric mucosa, increased bacterial load, induction of Treg cells in the stomach, increased IL-10 in the serum. Interestingly, B7-H1-/- mice showed less Treg cells and reduced bacterial loads after infection. These studies demonstrate how H. pylori T4SS components activate the p38 MAPK pathway, upregulate B7-H1 expression by GEC, and cause Treg cell induction; thus, contribute to establishing a persistent infection characteristic of H. pylori.},
	issn = {1932-6203},
	doi = {10.1371/journal.pone.0121841},
	author = {Lina, Taslima T and Alzahrani, Shatha and House, Jennifer and Yamaoka, Yoshio and Sharpe, Arlene H and Rampy, Bill A and Pinchuk, Irina V and Reyes, Victor E}
}
@article {542001,
	title = {ICOS:ICOS-ligand interaction is required for type 2 innate lymphoid cell function, homeostasis, and induction of airway hyperreactivity.},
	journal = {Immunity},
	volume = {42},
	number = {3},
	year = {2015},
	month = {2015 Mar 17},
	pages = {538-51},
	abstract = {Allergic asthma is caused by Th2-cell-type cytokines in response to allergen exposure. Type 2 innate lymphoid cells (ILC2s) are a newly identified subset of immune cells that, along with Th2 cells, contribute to the pathogenesis of asthma by producing copious amounts of IL-5 and IL-13, which cause eosinophilia and airway hyperreactivity (AHR), a cardinal feature of asthma. ILC2s express ICOS, a T cell costimulatory molecule with a currently unknown function. Here we showed that a lack of ICOS on murine ILC2s and blocking the ICOS:ICOS-ligand interaction in human ILC2s reduced AHR and lung inflammation. ILC2s expressed both ICOS and ICOS-ligand, and the ICOS:ICOS-ligand interaction promoted cytokine production and survival in ILC2s through STAT5 signaling. Thus, ICOS:ICOS-ligand signaling pathway is critically involved in ILC2 function and homeostasis.},
	keywords = {Animals, Asthma, Female, Gene Expression Regulation, Homeostasis, Humans, Immunity, Innate, Inducible T-Cell Co-Stimulator Ligand, Inducible T-Cell Co-Stimulator Protein, Interleukin-13, Interleukin-2, Interleukin-5, Interleukins, Lymphocytes, Mice, Transgenic, Respiratory System, Signal Transduction, STAT5 Transcription Factor},
	issn = {1097-4180},
	doi = {10.1016/j.immuni.2015.02.007},
	author = {Maazi, Hadi and Patel, Nisheel and Sankaranarayanan, Ishwarya and Suzuki, Yuzo and Rigas, Diamanda and Soroosh, Pejman and Freeman, Gordon J and Sharpe, Arlene H and Akbari, Omid}
}
@article {541991,
	title = {In vitro assay to sensitively measure T(FR) suppressive capacity and T(FH) stimulation of B cell responses.},
	journal = {Methods Mol Biol},
	volume = {1291},
	year = {2015},
	month = {2015},
	pages = {151-60},
	abstract = {T follicular helper (T(FH)) cells stimulate, whereas T follicular regulatory (T(FR)) cells inhibit, B cell responses. Despite the potent immunoregulatory roles for TFR cells in controlling the magnitude of antibody production, the precise mechanisms by which T(FR) cells exert their suppressive effects are not yet clear. The lack of specific assays to assess T(FR) cell function separately from differentiation has hindered progress in elucidating T(FR) cell function. This is due, in part, to difficulty in separating T(FR) cells from phenotypically similar, but functionally different, T(FH) cells. Here we describe an in vitro approach for sensitively and quantitatively assessing the capacity of T(FR) cells to suppress T(FH)-mediated B cell antibody production utilizing both ELISA and flow cytometry to measure B cell responses. Beyond assessing T(FR) function, this assay system can also be used to sensitively measure T(FH) stimulatory capacity as well as B cell function.},
	issn = {1940-6029},
	doi = {10.1007/978-1-4939-2498-1_13},
	author = {Sage, Peter T and Sharpe, Arlene H}
}
@article {541986,
	title = {The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells.},
	journal = {Elife},
	volume = {4},
	year = {2015},
	month = {2015},
	abstract = {The balance between Th17 and T regulatory (Treg) cells critically modulates immune homeostasis, with an inadequate Treg response contributing to inflammatory disease. Using an unbiased chemical biology approach, we identified a novel role for the dual specificity tyrosine-phosphorylation-regulated kinase DYRK1A in regulating this balance. Inhibition of DYRK1A enhances Treg differentiation and impairs Th17 differentiation without affecting known pathways of Treg/Th17 differentiation. Thus, DYRK1A represents a novel mechanistic node at the branch point between commitment to either Treg or Th17 lineages. Importantly, both Treg cells generated using the DYRK1A inhibitor harmine and direct administration of harmine itself potently attenuate inflammation in multiple experimental models of systemic autoimmunity and mucosal inflammation. Our results identify DYRK1A as a physiologically relevant regulator of Treg cell differentiation and suggest a broader role for other DYRK family members in immune homeostasis. These results are discussed in the context of human diseases associated with dysregulated DYRK activity.},
	issn = {2050-084X},
	doi = {10.7554/eLife.05920},
	author = {Khor, Bernard and Gagnon, John D and Goel, Gautam and Roche, Marly I and Conway, Kara L and Tran, Khoa and Aldrich, Leslie N and Sundberg, Thomas B and Paterson, Alison M and Mordecai, Scott and Dombkowski, David and Schirmer, Melanie and Tan, Pauline H and Bhan, Atul K and Roychoudhuri, Rahul and Restifo, Nicholas P and O{\textquoteright}Shea, John J and Medoff, Benjamin D and Shamji, Alykhan F and Schreiber, Stuart L and Sharpe, Arlene H and Shaw, Stanley Y and Xavier, Ramnik J}
}
@article {541966,
	title = {Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth.},
	journal = {Cell},
	volume = {162},
	number = {6},
	year = {2015},
	month = {2015 Sep 10},
	pages = {1242-56},
	abstract = {Therapeutic antibodies targeting programmed cell death 1 (PD-1) activate tumor-specific immunity and~have shown remarkable efficacy in the treatment of melanoma. Yet, little is known about tumor cell-intrinsic PD-1 pathway effects. Here, we show that murine and human melanomas contain PD-1-expressing cancer subpopulations and demonstrate that melanoma cell-intrinsic PD-1 promotes tumorigenesis, even in mice lacking adaptive immunity. PD-1 inhibition on melanoma cells by RNAi, blocking antibodies, or mutagenesis of melanoma-PD-1 signaling motifs suppresses tumor growth in immunocompetent, immunocompromised, and PD-1-deficient tumor graft recipient mice. Conversely, melanoma-specific PD-1 overexpression enhances tumorigenicity, as does engagement of melanoma-PD-1 by its ligand, PD-L1, whereas melanoma-PD-L1 inhibition or knockout of host-PD-L1 attenuate growth of PD-1-positive melanomas. Mechanistically, the melanoma-PD-1 receptor modulates downstream effectors of mTOR signaling. Our results identify melanoma cell-intrinsic functions of the PD-1:PD-L1 axis in tumor growth and suggest that blocking melanoma-PD-1 might contribute to the striking clinical efficacy of anti-PD-1 therapy.},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2015.08.052},
	author = {Kleffel, Sonja and Posch, Christian and Barthel, Steven R and Mueller, Hansgeorg and Schlapbach, Christoph and Guenova, Emmanuella and Elco, Christopher P and Lee, Nayoung and Juneja, Vikram R and Zhan, Qian and Lian, Christine G and Thomi, Rahel and Hoetzenecker, Wolfram and Cozzio, Antonio and Dummer, Reinhard and Mihm, Martin C and Flaherty, Keith T and Frank, Markus H and Murphy, George F and Sharpe, Arlene H and Kupper, Thomas S and Schatton, Tobias}
}
@article {541981,
	title = {T follicular regulatory cells in the regulation of B cell responses.},
	journal = {Trends Immunol},
	volume = {36},
	number = {7},
	year = {2015},
	month = {2015 Jul},
	pages = {410-8},
	abstract = {High affinity antibodies result from interactions between B cells and T follicular helper (Tfh) cells in germinal centers (GCs). Recent studies have identified an effector subset of T regulatory cells termed T follicular regulatory (Tfr) cells that specifically controls GC responses by suppressing Tfh and B cells. The discovery of Tfr cells has shed new light on pathways regulating humoral immunity that enable potent and specific responses to pathogens while restricting autoimmunity. Here, we review the current understanding of the cellular and molecular mechanisms underlying the differentiation and function of Tfr cells. In this context we discuss recent insights into the role of Tfh cells in disease, how this knowledge may be translated therapeutically, and important areas of further research.},
	issn = {1471-4981},
	doi = {10.1016/j.it.2015.05.005},
	author = {Sage, Peter T and Sharpe, Arlene H}
}
@article {542086,
	title = {GEF-H1 controls microtubule-dependent sensing of nucleic acids for antiviral host defenses.},
	journal = {Nat Immunol},
	volume = {15},
	number = {1},
	year = {2014},
	month = {2014 Jan},
	pages = {63-71},
	abstract = {Detailed understanding of the signaling intermediates that confer the sensing of intracellular viral nucleic acids for induction of type I interferons is critical for strategies to curtail viral mechanisms that impede innate immune defenses. Here we show that the activation of the microtubule-associated guanine nucleotide exchange factor GEF-H1, encoded by Arhgef2, is essential for sensing of foreign RNA by RIG-I-like receptors. Activation of GEF-H1 controls RIG-I-dependent and Mda5-dependent phosphorylation of IRF3 and induction of IFN-β expression in macrophages. Generation of Arhgef2(-/-) mice revealed a pronounced signaling defect that prevented antiviral host responses to encephalomyocarditis virus and influenza A virus. Microtubule networks sequester GEF-H1 that upon activation is released to enable antiviral signaling by intracellular nucleic acid detection pathways.},
	keywords = {Animals, Cercopithecus aethiops, COS Cells, DEAD-box RNA Helicases, Gene Expression, Green Fluorescent Proteins, HEK293 Cells, Humans, Immunity, Innate, Immunoblotting, Influenza A virus, Interferon Regulatory Factor-3, Interferon-beta, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Confocal, Microtubules, Phosphorylation, Reverse Transcriptase Polymerase Chain Reaction, Rho Guanine Nucleotide Exchange Factors, RNA, Viral, Signal Transduction},
	issn = {1529-2916},
	doi = {10.1038/ni.2766},
	author = {Chiang, Hao-Sen and Zhao, Yun and Song, Joo-Hye and Liu, Song and Wang, Ninghai and Terhorst, Cox and Sharpe, Arlene H and Basavappa, Megha and Jeffrey, Kate L and Reinecker, Hans-Christian}
}
@article {542076,
	title = {Inclusion of CD80 in HSV targets the recombinant virus to PD-L1 on DCs and allows productive infection and robust immune responses.},
	journal = {PLoS One},
	volume = {9},
	number = {1},
	year = {2014},
	month = {2014},
	pages = {e87617},
	abstract = {CD80 plays a critical role in stimulation of T cells and subsequent control of infection. To investigate the effect of CD80 on HSV-1 infection, we constructed a recombinant HSV-1 virus that expresses two copies of the CD80 gene in place of the latency associated transcript (LAT). This mutant virus (HSV-CD80) expressed high levels of CD80 and had similar virus replication kinetics as control viruses in rabbit skin cells. In contrast to parental virus, this CD80 expressing recombinant virus replicated efficiently in immature dendritic cells (DCs). Additionally, the susceptibility of immature DCs to HSV-CD80 infection was mediated by CD80 binding to PD-L1 on DCs. This interaction also contributed to a significant increase in T cell activation. Taken together, these results suggest that inclusion of CD80 as a vaccine adjuvant may promote increased vaccine efficacy by enhancing the immune response directly and also indirectly by targeting to DC.},
	keywords = {Adjuvants, Immunologic, Animals, Antigens, CD274, Antigens, CD80, Blotting, Southern, Dendritic Cells, DNA Primers, Flow Cytometry, Fluorescent Antibody Technique, Genetic Engineering, Herpes Simplex, Herpesvirus 1, Human, MicroRNAs, Rabbits, Real-Time Polymerase Chain Reaction, Recombination, Genetic, Viral Vaccines},
	issn = {1932-6203},
	doi = {10.1371/journal.pone.0087617},
	author = {Mott, Kevin R and Allen, Sariah J and Zandian, Mandana and Akbari, Omid and Hamrah, Pedram and Maazi, Hadi and Wechsler, Steven L and Sharpe, Arlene H and Freeman, Gordon J and Ghiasi, Homayon}
}
@article {542061,
	title = {Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade.},
	journal = {Cancer Immunol Res},
	volume = {2},
	number = {7},
	year = {2014},
	month = {2014 Jul},
	pages = {643-54},
	abstract = {BRAF-targeted therapy results in objective responses in the majority of patients; however, the responses are short lived (\~{}6 months). In contrast, treatment with immune checkpoint inhibitors results in a lower response rate, but the responses tend to be more durable. BRAF inhibition results in a more favorable tumor microenvironment in patients, with an increase in CD8(+) T-cell infiltrate and a decrease in immunosuppressive cytokines. There is also increased expression of the immunomodulatory molecule PDL1, which may contribute to the resistance. On the basis of these findings, we hypothesized that BRAF-targeted therapy may synergize with the PD1 pathway blockade to enhance antitumor immunity. To test this hypothesis, we developed a BRAF(V600E)/Pten(-/-) syngeneic tumor graft immunocompetent mouse model in which BRAF inhibition leads to a significant increase in the intratumoral CD8(+) T-cell density and cytokine production, similar to the effects of BRAF inhibition in patients. In this model, CD8(+) T cells were found to play a critical role in the therapeutic effect of BRAF inhibition. Administration of anti-PD1 or anti-PDL1 together with a BRAF inhibitor led to an enhanced response, significantly prolonging survival and slowing tumor growth, as well as significantly increasing the number and activity of tumor-infiltrating lymphocytes. These results demonstrate synergy between combined BRAF-targeted therapy and immune checkpoint blockade. Although clinical trials combining these two strategies are ongoing, important questions still remain unanswered. Further studies using this new melanoma mouse model may provide therapeutic insights, including optimal timing and sequence of therapy.},
	keywords = {Animals, Antibodies, Monoclonal, Antigens, CD274, Antigens, Neoplasm, Antineoplastic Combined Chemotherapy Protocols, CD8-Positive T-Lymphocytes, Cell Line, Tumor, CTLA-4 Antigen, Cytokines, Dose-Response Relationship, Drug, Humans, Immunocompetence, Indoles, Lymphocyte Count, Lymphocytes, Tumor-Infiltrating, Male, Melanoma, Mice, Inbred C57BL, Middle Aged, Proto-Oncogene Proteins B-raf, Sulfonamides, T-Lymphocytes, Regulatory, Tumor Escape, Xenograft Model Antitumor Assays},
	issn = {2326-6074},
	doi = {10.1158/2326-6066.CIR-13-0215},
	author = {Cooper, Zachary A and Juneja, Vikram R and Sage, Peter T and Frederick, Dennie T and Piris, Adriano and Mitra, Devarati and Lo, Jennifer A and Hodi, F Stephen and Freeman, Gordon J and Bosenberg, Marcus W and McMahon, Martin and Flaherty, Keith T and Fisher, David E and Sharpe, Arlene H and Wargo, Jennifer A}
}
@article {542066,
	title = {RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance.},
	journal = {J Exp Med},
	volume = {211},
	number = {5},
	year = {2014},
	month = {2014 May 5},
	pages = {943-59},
	abstract = {We report that programmed death ligand 2 (PD-L2), a known ligand of PD-1, also binds to repulsive guidance molecule b (RGMb), which was originally identified in the nervous system as a co-receptor for bone morphogenetic proteins (BMPs). PD-L2 and BMP-2/4 bind to distinct sites on RGMb. Normal resting lung interstitial macrophages and alveolar epithelial cells express high levels of RGMb mRNA, whereas lung dendritic cells express PD-L2. Blockade of the RGMb-PD-L2 interaction markedly impaired the development of respiratory tolerance by interfering with the initial T cell expansion required for respiratory tolerance. Experiments with PD-L2-deficient mice showed that PD-L2 expression on non-T cells was critical for respiratory tolerance, but expression on T cells was not required. Because PD-L2 binds to both PD-1, which inhibits antitumor immunity, and to RGMb, which regulates respiratory immunity, targeting the PD-L2 pathway has therapeutic potential for asthma, cancer, and other immune-mediated disorders. Understanding this pathway may provide insights into how to optimally modulate the PD-1 pathway in cancer immunotherapy while minimizing adverse events.},
	keywords = {Animals, Bone Morphogenetic Protein 2, Cell Line, Tumor, Epithelial Cells, Humans, Immune Tolerance, Lung, Macrophages, Alveolar, Mice, Nerve Tissue Proteins, Programmed Cell Death 1 Ligand 2 Protein, Protein Binding},
	issn = {1540-9538},
	doi = {10.1084/jem.20130790},
	author = {Xiao, Yanping and Yu, Sanhong and Zhu, Baogong and Bedoret, Denis and Bu, Xia and Francisco, Loise M and Hua, Ping and Duke-Cohan, Jonathan S and Umetsu, Dale T and Sharpe, Arlene H and DeKruyff, Rosemarie H and Freeman, Gordon J}
}
@article {542071,
	title = {Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses.},
	journal = {Immunity},
	volume = {40},
	number = {4},
	year = {2014},
	month = {2014 Apr 17},
	pages = {569-81},
	abstract = {Foxp3(+) T regulatory (Treg) cells regulate immune responses and maintain self-tolerance. Recent work shows that Treg cells are comprised of many subpopulations with specialized regulatory functions. Here we identified Foxp3(+) T cells expressing the coinhibitory molecule TIGIT as a distinct Treg cell subset that specifically suppresses proinflammatory T helper 1 (Th1) and Th17 cell, but not Th2 cell responses. Transcriptional profiling characterized TIGIT(+) Treg cells as an activated Treg cell subset with high expression of Treg signature genes. Ligation of TIGIT on Treg cells induced expression of the effector molecule fibrinogen-like protein 2 (Fgl2), which promoted Treg-cell-mediated suppression of T effector cell proliferation. In addition, Fgl2 was necessary to prevent suppression of Th2 cytokine production in a model of allergic airway inflammation. TIGIT expression therefore identifies a Treg cell subset that demonstrates selectivity for suppression of Th1 and Th17 cell but not Th2 cell responses.},
	keywords = {Animals, Cell Proliferation, Cells, Cultured, Cytokines, Eosinophils, Fibrinogen, Forkhead Transcription Factors, Gene Expression Profiling, Gene Expression Regulation, Immunosuppression, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Receptors, Immunologic, Respiratory Hypersensitivity, T-Lymphocyte Subsets, T-Lymphocytes, Regulatory, Th1-Th2 Balance},
	issn = {1097-4180},
	doi = {10.1016/j.immuni.2014.02.012},
	author = {Joller, Nicole and Lozano, Ester and Burkett, Patrick R and Patel, Bonny and Xiao, Sheng and Zhu, Chen and Xia, Junrong and Tan, Tze G and Sefik, Esen and Yajnik, Vijay and Sharpe, Arlene H and Quintana, Francisco J and Mathis, Diane and Benoist, Christophe and Hafler, David A and Kuchroo, Vijay K}
}
@article {542021,
	title = {Balance and imbalance in the immune system: life on the edge.},
	journal = {Immunity},
	volume = {41},
	number = {5},
	year = {2014},
	month = {2014 Nov 20},
	pages = {682-4},
	abstract = {CTLA-4 is a key immune checkpoint in maintaining self-tolerance, which can be co-opted by cancer to evade immune attack. In Science, Kuehn et~al. (2014) describe clinical manifestations from inherited heterozygous CTLA4 mutations, and some are reminiscent of immune-related consequences from anti-CTLA-4 cancer therapy.},
	keywords = {Animals, CTLA-4 Antigen, Female, Germ-Line Mutation, Haploinsufficiency, Humans, Immune System Diseases, Immunity, Male},
	issn = {1097-4180},
	doi = {10.1016/j.immuni.2014.11.005},
	author = {Topalian, Suzanne L and Sharpe, Arlene H}
}
@article {542036,
	title = {Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens.},
	journal = {Nature},
	volume = {515},
	number = {7528},
	year = {2014},
	month = {2014 Nov 27},
	pages = {577-81},
	abstract = {The immune system influences the fate of developing cancers by not only functioning as a tumour promoter that facilitates cellular transformation, promotes tumour growth and sculpts tumour cell immunogenicity, but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion. Yet, clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer-induced immunosuppression. In many individuals, immunosuppression is mediated by cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), two immunomodulatory receptors expressed on T cells. Monoclonal-antibody-based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits-including durable responses--to patients with different malignancies. However, little is known about the identity of the tumour antigens that function as the targets of T cells activated by checkpoint blockade immunotherapy and whether these antigens can be used to generate vaccines that are highly tumour-specific. Here we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T-cell rejection antigens following anti-PD-1 and/or anti-CTLA-4 therapy of mice bearing progressively growing sarcomas, and we show that therapeutic synthetic long-peptide vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Although mutant tumour-antigen-specific T cells are present in progressively growing tumours, they are reactivated following treatment with anti-PD-1 and/or anti-CTLA-4 and display some overlapping but mostly treatment-specific transcriptional profiles, rendering them capable of mediating tumour rejection. These results reveal that tumour-specific mutant antigens are not only important targets of checkpoint blockade therapy, but they can also be used to develop personalized cancer-specific vaccines and to probe the mechanistic underpinnings of different checkpoint blockade treatments.},
	keywords = {Animals, Antibodies, Monoclonal, Antigens, Neoplasm, Cancer Vaccines, CD8-Positive T-Lymphocytes, Cell Cycle Checkpoints, Epitopes, Immunotherapy, Male, Mice, Sarcoma, Vaccines, Synthetic},
	issn = {1476-4687},
	doi = {10.1038/nature13988},
	author = {Gubin, Matthew M and Zhang, Xiuli and Schuster, Heiko and Caron, Etienne and Ward, Jeffrey P and Noguchi, Takuro and Ivanova, Yulia and Hundal, Jasreet and Arthur, Cora D and Krebber, Willem-Jan and Mulder, Gwenn E and Toebes, Mireille and Vesely, Matthew D and Lam, Samuel S K and Korman, Alan J and Allison, James P and Freeman, Gordon J and Sharpe, Arlene H and Pearce, Erika L and Schumacher, Ton N and Aebersold, Ruedi and Rammensee, Hans-Georg and Melief, Cornelis J M and Mardis, Elaine R and Gillanders, William E and Artyomov, Maxim N and Schreiber, Robert D}
}
@article {542046,
	title = {Circulating T follicular regulatory and helper cells have memory-like properties.},
	journal = {J Clin Invest},
	volume = {124},
	number = {12},
	year = {2014},
	month = {2014 Dec},
	pages = {5191-204},
	abstract = {Follicular Tregs (Tfr cells) inhibit antibody production, whereas follicular Th cells (Tfh cells) stimulate it. Tfr cells are found in blood; however, relatively little is known about the developmental signals for these cells or their functions. Here we demonstrated that circulating Tfr and Tfh cells share properties of memory cells and are distinct from effector Tfr and Tfh cells found within lymph nodes (LNs). Circulating memory-like Tfh cells were potently reactivated by DCs, homed to germinal centers, and produced more cytokines than did effector LN Tfh cells. Circulating memory-like Tfr cells persisted for long periods of time in vivo and homed to germinal centers after reactivation. Effector LN Tfr cells suppressed Tfh cell activation and production of cytokines, including IL-21, and inhibited class switch recombination and B cell activation. The suppressive function of this population was not dependent on specific antigen. Similar to LN effector Tfr cells, circulating Tfr cells also suppressed B and Tfh cells, but with a much lower capacity. Our data indicate that circulating memory-like Tfr cells are less suppressive than LN Tfr cells and circulating memory-like Tfh cells are more potent than LN effector Tfh cells; therefore, these circulating populations can provide rapid and robust systemic B cell help during secondary antigen exposure.},
	keywords = {Animals, Antibody Formation, B-Lymphocytes, Immunoglobulin Class Switching, Immunologic Memory, Interleukins, Lymph Nodes, Lymphocyte Activation, Mice, Mice, Knockout, T-Lymphocytes, Regulatory},
	issn = {1558-8238},
	doi = {10.1172/JCI76861},
	author = {Sage, Peter T and Alvarez, David and Godec, Jernej and von Andrian, Ulrich H and Sharpe, Arlene H}
}
@article {542056,
	title = {Coinfection with Streptococcus pneumoniae modulates the B cell response to influenza virus.},
	journal = {J Virol},
	volume = {88},
	number = {20},
	year = {2014},
	month = {2014 Oct},
	pages = {11995-2005},
	abstract = {Pathogen-specific antibodies (Abs) protect against respiratory infection with influenza A virus (IAV) and Streptococcus pneumoniae and are the basis of effective vaccines. Sequential or overlapping coinfections with both pathogens are common, yet the impact of coinfection on the generation and maintenance of Ab responses is largely unknown. We report here that the B cell response to IAV is altered in mice coinfected with IAV and S. pneumoniae and that this response differs, depending on the order of pathogen exposure. In mice exposed to S. pneumoniae prior to IAV, the initial virus-specific germinal center (GC) B cell response is significantly enhanced in the lung-draining mediastinal lymph node and spleen, and there is an increase in CD4(+) T follicular helper (TFH) cell numbers. In contrast, secondary S. pneumoniae infection exaggerates early antiviral antibody-secreting cell formation, and at later times, levels of GCs, TFH cells, and antiviral serum IgG are elevated. Mice exposed to S. pneumoniae prior to IAV do not maintain the initially robust GC response in secondary lymphoid organs and exhibit reduced antiviral serum IgG with diminished virus neutralization activity a month after infection. Our data suggest that the history of pathogen exposures can critically affect the generation of protective antiviral Abs and may partially explain the differential susceptibility to and disease outcomes from IAV infection in humans. Importance: Respiratory tract coinfections, specifically those involving influenza A viruses and Streptococcus pneumoniae, remain a top global health burden. We sought to determine how S. pneumoniae coinfection modulates the B cell immune response to influenza virus since antibodies are key mediators of protection.},
	keywords = {Animals, B-Lymphocytes, Female, Flow Cytometry, Germinal Center, Humans, Influenza A virus, Influenza, Human, Mice, Mice, Inbred BALB C, Pneumococcal Infections, Streptococcus pneumoniae},
	issn = {1098-5514},
	doi = {10.1128/JVI.01833-14},
	author = {Wolf, Amaya I and Strauman, Maura C and Mozdzanowska, Krystyna and Whittle, James R R and Williams, Katie L and Sharpe, Arlene H and Weiser, Jeffrey N and Caton, Andrew J and Hensley, Scott E and Erikson, Jan}
}
@article {542016,
	title = {The coinhibitory receptor CTLA-4 controls B cell responses by modulating T follicular helper, T follicular regulatory, and T regulatory cells.},
	journal = {Immunity},
	volume = {41},
	number = {6},
	year = {2014},
	month = {2014 Dec 18},
	pages = {1026-39},
	abstract = {The receptor CTLA-4 has been implicated in controlling B cell responses, but the mechanisms by which CTLA-4 regulates antibody production are not known. Here we showed deletion of CTLA-4 in adult mice increased Tfh and Tfr cell numbers and augmented B cell responses. In the effector phase, loss of CTLA-4 on Tfh cells resulted in heightened B cell responses, whereas loss of CTLA-4 on Tfr cells resulted in defective suppression of antigen-specific antibody responses. We also found that non-Tfr Treg cells could suppress B cell responses through CTLA-4 and that Treg and/or Tfr cells might downregulate B7-2 on B cells outside germinal centers as a means of suppression. Within the germinal center, however, Tfr cells potently suppress B cells through CTLA-4, but with a mechanism independent of altering B7-1 or B7-2. Thus, we identify multifaceted regulatory roles for CTLA-4 in Tfh, Tfr, and Treg cells, which together control humoral immunity.},
	keywords = {Animals, Antibody Formation, Antigens, CD80, Antigens, CD86, B-Lymphocytes, Cell Differentiation, Cells, Cultured, CTLA-4 Antigen, Down-Regulation, Germinal Center, Immune Tolerance, Mice, Mice, Inbred Strains, Mice, Knockout, Mice, Transgenic, T-Lymphocytes, Helper-Inducer, T-Lymphocytes, Regulatory},
	issn = {1097-4180},
	doi = {10.1016/j.immuni.2014.12.005},
	author = {Sage, Peter T and Paterson, Alison M and Lovitch, Scott B and Sharpe, Arlene H}
}
@article {542051,
	title = {Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection.},
	journal = {J Exp Med},
	volume = {211},
	number = {9},
	year = {2014},
	month = {2014 Aug 25},
	pages = {1905-18},
	abstract = {Regulatory T (T reg) cells are critical for preventing autoimmunity mediated by self-reactive T cells, but their role in modulating immune responses during chronic viral infection is not well defined. To address this question and to investigate a role for T reg cells in exhaustion of virus-specific CD8 T cells, we depleted T reg cells in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). T reg cell ablation resulted in 10-100-fold expansion of functional LCMV-specific CD8 T cells. Rescue of exhausted CD8 T cells was dependent on cognate antigen, B7 costimulation, and conventional CD4 T cells. Despite the striking recovery of LCMV-specific CD8 T cell responses, T reg cell depletion failed to diminish viral load. Interestingly, T reg cell ablation triggered up-regulation of the molecule programmed cell death ligand-1 (PD-L1), which upon binding PD-1 on T cells delivers inhibitory signals. Increased PD-L1 expression was observed especially on LCMV-infected cells, and combining T reg cell depletion with PD-L1 blockade resulted in a significant reduction in viral titers, which was more pronounced than that upon PD-L1 blockade alone. These results suggest that T reg cells effectively maintain CD8 T cell exhaustion, but blockade of the PD-1 inhibitory pathway is critical for elimination of infected cells.},
	keywords = {Animals, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Chronic Disease, Dendritic Cells, Lymphocyte Activation, Lymphocyte Depletion, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Mice, Mice, Inbred C57BL, Mice, Transgenic, Programmed Cell Death 1 Receptor, T-Lymphocytes, Regulatory, Up-Regulation},
	issn = {1540-9538},
	doi = {10.1084/jem.20132577},
	author = {Penaloza-MacMaster, Pablo and Kamphorst, Alice O and Wieland, Andreas and Araki, Koichi and Iyer, Smita S and West, Erin E and O{\textquoteright}Mara, Leigh and Yang, Shu and Konieczny, Bogumila T and Sharpe, Arlene H and Freeman, Gordon J and Rudensky, Alexander Y and Ahmed, Rafi}
}
@article {542111,
	title = {B7h (ICOS-L) maintains tolerance at the fetomaternal interface.},
	journal = {Am J Pathol},
	volume = {182},
	number = {6},
	year = {2013},
	month = {2013 Jun},
	pages = {2204-13},
	abstract = {In a successful pregnancy, the semiallogeneic fetus is not rejected by the maternal immune system, which implies tolerance mechanisms protecting fetal tissues from maternal immune attack. Here we report that the ICOS-B7h costimulatory pathway plays a critical role in maintaining the equilibrium at the fetomaternal interface. Blockade of this pathway increased fetal resorption and decreased fetal survival in an allogeneic pregnancy model (CBA female {\texttimes} B6 male). Locally in the placenta, levels of regulatory markers such as IDO and TGF-β1 were reduced after anti-B7h monoclonal antibody treatment, whereas levels of effector cytokines (eg, IFN-γ) were significantly increased. In secondary lymphoid organs, enhanced IFN-γ and granzyme B production (predominantly by CD8(+) T cells) was observed in the anti-B7h-treated group. The deleterious effect of B7h blockade in pregnancy was maintained only in CD4 knockout mice, not in CD8 knockout mice, which suggests a role for CD8(+) T~cells in immune regulation by the ICOS-B7h pathway. In accord, regulatory CD8(+) T cells (in particular, CD8(+)CD103(+) cells) were significantly decreased after anti-B7h monoclonal antibody treatment, and adoptive transfer of this subset abrogated the deleterious effect of B7h blockade in fetomaternal tolerance. Taken together, these data support the hypothesis that B7h blockade abrogates tolerance at the fetomaternal interface by enhancing CD8(+) effector response and reducing local immunomodulation mediated by CD8(+) regulatory T cells.},
	keywords = {Adoptive Transfer, Animals, Antibodies, Monoclonal, CD8-Positive T-Lymphocytes, CTLA-4 Antigen, Cytokines, Embryo Loss, Female, Immune Tolerance, Indoleamine-Pyrrole 2,3,-Dioxygenase, Inducible T-Cell Co-Stimulator Ligand, Litter Size, Lymph Nodes, Maternal-Fetal Exchange, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Knockout, Placenta, Pregnancy, Spleen, T-Lymphocyte Subsets, T-Lymphocytes, Regulatory},
	issn = {1525-2191},
	doi = {10.1016/j.ajpath.2013.02.014},
	author = {Riella, Leonardo V and Dada, Shirine and Chabtini, Lola and Smith, Brian and Huang, Lei and Dakle, Pranal and Mfarrej, Bechara and D{\textquoteright}Addio, Francesca and Adams, La-Tonya and Kochupurakkal, Nora and Vergani, Andrea and Fiorina, Paolo and Mellor, Andrew L and Sharpe, Arlene H and Yagita, Hideo and Guleria, Indira}
}
@article {542136,
	title = {Brief report: increased expression of a short splice variant of CTLA-4 exacerbates lupus in MRL/lpr mice.},
	journal = {Arthritis Rheum},
	volume = {65},
	number = {3},
	year = {2013},
	month = {2013 Mar},
	pages = {764-9},
	abstract = {OBJECTIVE: CTLA-4 is a negative regulator of the immune response expressed by regulatory T (Treg) cells and activated T cells. Polymorphisms in the CTLA4 gene have been associated with autoimmune diseases, including systemic lupus erythematosus. Disease-associated polymorphisms have been shown to affect the production of the different CTLA-4 variants through an effect on alternative splicing. This study was undertaken to evaluate the role of the 1/4 CTLA-4 isoform in lupus-prone mice.

METHODS: We generated an MRL/lpr mouse strain that transgenically overexpresses a short isoform of CTLA-4 (1/4 CTLA-4) by backcrossing C57BL/6.1/4CTLA-4-transgenic mice to the MRL/lpr strain for 9 generations. A new antibody was generated to detect the expression of the 1/4 CTLA-4 isoform. Routine methods were used to evaluate kidney damage, humoral immunity, and cellular immunity.

RESULTS: Expression of the 1/4 CTLA-4 isoform accelerated autoimmune disease. Transgenic mice died earlier, had more severe renal disease, and had higher titers of anti-double-stranded DNA antibodies than wild-type MRL/lpr mice. The acceleration of autoimmunity and disease pathology associated with the presence of the short (1/4) isoform of CTLA-4 was linked to increased numbers of activated T cells and B cells and heightened interferon-γ production, but not to altered expression of the full-length CTLA-4 molecule or Treg cell numbers.

CONCLUSION: Our results indicate that the presence of the alternatively spliced 1/4 CTLA-4 isoform can further promote autoimmunity and autoimmune pathology in lupus-prone mice and suggest that altered splicing of CTLA4 contributes to the expression of autoimmune disease.},
	keywords = {Animals, Autoimmunity, B-Lymphocytes, CTLA-4 Antigen, Female, Gene Expression, Interferon-gamma, Lupus Erythematosus, Systemic, Lymphocyte Activation, Male, Mice, Mice, Inbred C57BL, Mice, Inbred MRL lpr, RNA Splice Sites, T-Lymphocytes, Regulatory},
	issn = {1529-0131},
	doi = {10.1002/art.37790},
	author = {Ichinose, Kunihiro and Zhang, Zheng and Koga, Tomohiro and Juang, Yuang-Taung and Kis-T{\'o}th, Katalin and Sharpe, Arlene H and Kuchroo, Vijay and Crisp{\'\i}n, Jos{\'e} C and Tsokos, George C}
}
@article {542126,
	title = {Circulatory antigen processing by mucosal dendritic cells controls CD8(+) T cell activation.},
	journal = {Immunity},
	volume = {38},
	number = {1},
	year = {2013},
	month = {2013 Jan 24},
	pages = {153-65},
	abstract = {Circulatory antigens transit through the small intestine via the fenestrated capillaries in the lamina propria prior to entering into the draining lymphatics. But whether or how this process controls mucosal immune responses remains unknown. Here we demonstrate that dendritic cells (DCs) of the lamina propria can sample and process both circulatory and luminal antigens. Surprisingly, antigen cross-presentation by resident CX3CR1(+) DCs induced differentiation of precursor cells into CD8(+) T~cells that expressed interleukin-10 (IL-10), IL-13, and IL-9 and could migrate into adjacent compartments. We conclude that lamina propria CX3CR1(+) DCs facilitate the surveillance of circulatory antigens and act as a conduit for the processing of self- and intestinally absorbed antigens, leading to the induction of CD8(+) T~cells, that partake in the control of T~cell activation during mucosal immune responses.},
	keywords = {Animals, Antigen Presentation, Antigens, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Differentiation, Cross-Priming, Dendritic Cells, Enteritis, Epitopes, T-Lymphocyte, Intestinal Mucosa, Intestine, Small, Lymphocyte Activation, Mice, Receptors, Chemokine},
	issn = {1097-4180},
	doi = {10.1016/j.immuni.2012.09.018},
	author = {Chang, Sun-Young and Song, Joo-Hye and Guleng, Bayasi and Cotoner, Carmen Alonso and Arihiro, Seiji and Zhao, Yun and Chiang, Hao-Sen and O{\textquoteright}Keeffe, Michael and Liao, Gongxian and Karp, Christopher L and Kweon, Mi-Na and Sharpe, Arlene H and Bhan, Atul and Terhorst, Cox and Reinecker, Hans-Christian}
}
@article {542121,
	title = {Distinct populations of innate CD8+ T cells revealed in a CXCR3 reporter mouse.},
	journal = {J Immunol},
	volume = {190},
	number = {5},
	year = {2013},
	month = {2013 Mar 1},
	pages = {2229-40},
	abstract = {CXCR3, expressed mainly on activated T and NK cells, is implicated in a host of immunological conditions and can contribute either to disease resolution or pathology. We report the generation and characterization of a novel CXCR3 internal ribosome entry site bicistronic enhanced GFP reporter (CIBER) mouse in which enhanced GFP expression correlates with surface levels of CXCR3. Using CIBER mice, we identified two distinct populations of innate CD8(+) T cells based on constitutive expression of CXCR3. We demonstrate that CXCR3(+) innate CD8(+) T cells preferentially express higher levels of Ly6C and CD122, but lower levels of CCR9 compared with CXCR3(-) innate CD8(+) T cells. Furthermore, we show that CXCR3(+) innate CD8(+) T cells express higher transcript levels of antiapoptotic but lower levels of proapoptotic factors, respond more robustly to IL-2 and IL-15, and produce significantly more IFN-γ and granzyme B. Interestingly, CXCR3(+) innate CD8(+) T cells do not respond to IL-12 or IL-18 alone, but produce significant amounts of IFN-γ on stimulation with a combination of these cytokines. Taken together, these findings demonstrate that CXCR3(+) and CXCR3(-) innate CD8(+) T cells are phenotypically and functionally distinct. These newly generated CIBER mice provide a novel tool for studying the role of CXCR3 and CXCR3-expressing cells in vivo.},
	keywords = {Animals, Antigens, Ly, Apoptosis Regulatory Proteins, CD8-Positive T-Lymphocytes, Cell Lineage, Cell Movement, Cell Proliferation, Cytokines, Founder Effect, Gene Expression, Genes, Reporter, Green Fluorescent Proteins, Immunity, Innate, Interleukin-2 Receptor beta Subunit, Male, Mice, Mice, Transgenic, Microscopy, Video, Receptors, CCR, Receptors, CXCR3},
	issn = {1550-6606},
	doi = {10.4049/jimmunol.1201170},
	author = {Oghumu, Steve and Dong, Ran and Varikuti, Sanjay and Shawler, Todd and Kampfrath, Thomas and Terrazas, Cesar A and Lezama-Davila, Claudio and Ahmer, Brian M M and Whitacre, Caroline C and Rajagopalan, Sanjay and Locksley, Richard and Sharpe, Arlene H and Satoskar, Abhay R}
}
@article {542116,
	title = {Lack of PD-L1 expression by iNKT cells improves the course of influenza A infection.},
	journal = {PLoS One},
	volume = {8},
	number = {3},
	year = {2013},
	month = {2013},
	pages = {e59599},
	abstract = {There is evidence indicating that invariant Natural Killer T (iNKT) cells play an important role in defense against influenza A virus (IAV). However, the effect of inhibitory receptor, programmed death-1 (PD-1), and its ligands, programmed death ligand (PD-L) 1 and 2 on iNKT cells in protection against IAV remains to be elucidated. Here we investigated the effects of these co-stimulatory molecules on iNKT cells in the response to influenza. We discovered that compare to the wild type, PD-L1 deficient mice show reduced sensitivity to IAV infection as evident by reduced weight loss, decreased pulmonary inflammation and cellular infiltration. In contrast, PD-L2 deficient mice showed augmented weight loss, pulmonary inflammation and cellular infiltration compare to the wild type mice after influenza infection. Adoptive transfer of iNKT cells from wild type, PD-L1 or PD-L2 deficient mice into iNKT cell deficient mice recapitulated these findings. Interestingly, in our transfer system PD-L1(-/-)-derived iNKT cells produced high levels of interferon-gamma whereas PD-L2(-/-)-derived iNKT cells produced high amounts of interleukin-4 and 13 suggesting a role for these cytokines in sensitivity to influenza. We identified that PD-L1 negatively regulates the frequency of iNKT cell subsets in the lungs of IAV infected mice. Altogether, these results demonstrate that lack of PD-L1 expression by iNKT cells reduces the sensitivity to IAV and that the presence of PD-L2 is important for dampening the deleterious inflammatory responses after IAV infection. Our findings potentially have clinical implications for developing new therapies for influenza.},
	keywords = {Animals, Antigens, CD274, Cytokines, Dendritic Cells, Female, Gene Expression Regulation, Gene Knockout Techniques, Influenza A Virus, H1N1 Subtype, Lung, Mice, Mice, Inbred BALB C, Natural Killer T-Cells, Orthomyxoviridae Infections, Programmed Cell Death 1 Ligand 2 Protein},
	issn = {1932-6203},
	doi = {10.1371/journal.pone.0059599},
	author = {Maazi, Hadi and Singh, Abinav K and Speak, Anneliese O and Lombardi, Vincent and Lam, Jonathan and Khoo, Bryant and Inn, Kyung Soo and Sharpe, Arlene H and Jung, Jae U and Akbari, Omid}
}
@article {542131,
	title = {The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood.},
	journal = {Nat Immunol},
	volume = {14},
	number = {2},
	year = {2013},
	month = {2013 Feb},
	pages = {152-61},
	abstract = {CD4(+)CXCR5(+)Foxp3(+) follicular regulatory T cells (T(FR) cells) inhibit humoral immunity mediated by CD4(+)CXCR5(+)Foxp3(-) follicular helper T cells (T(FH) cells). Although the inhibitory receptor PD-1 is expressed by both cell types, its role in the differentiation of T(FR) cells is unknown. Here we found that mice deficient in PD-1 and its ligand PD-L1 had a greater abundance of T(FR) cells in the lymph nodes and that those T(FR) cells had enhanced suppressive ability. We also found substantial populations of T(FR) cells in mouse blood and demonstrated that T(FR) cells in the blood homed to lymph nodes and potently inhibited T(FH) cells in vivo. T(FR) cells in the blood required signaling via the costimulatory receptors CD28 and ICOS but were inhibited by PD-1 and PD-L1. Our findings demonstrate mechanisms by which the PD-1 pathway regulates antibody production and help reconcile inconsistencies surrounding the role of this pathway in humoral immunity.},
	keywords = {Animals, Antibody Formation, Antigens, CD274, Antigens, CD28, Cell Communication, Cell Differentiation, Gene Expression Regulation, Immunity, Humoral, Inducible T-Cell Co-Stimulator Protein, Lymph Nodes, Lymphocyte Count, Mice, Mice, Transgenic, Programmed Cell Death 1 Receptor, Signal Transduction, T-Lymphocytes, Helper-Inducer, T-Lymphocytes, Regulatory},
	issn = {1529-2916},
	doi = {10.1038/ni.2496},
	author = {Sage, Peter T and Francisco, Loise M and Carman, Christopher V and Sharpe, Arlene H}
}
@article {542091,
	title = {BRAF inhibition is associated with increased clonality in tumor-infiltrating lymphocytes.},
	journal = {Oncoimmunology},
	volume = {2},
	number = {10},
	year = {2013},
	month = {2013 Oct 1},
	pages = {e26615},
	abstract = {There have been significant advances with regard to BRAF-targeted therapies against metastatic melanoma. However, the majority of patients receiving BRAF inhibitors (BRAFi) manifest disease progression within a year. We have recently shown that melanoma patients treated with BRAFi exhibit an increase in melanoma-associated antigens and in CD8+ tumor-infiltrating lymphocytes in response to therapy. To characterize such a T-cell infiltrate, we analyzed the complementarity-determining region 3 (CDR3) of rearranged T-cell receptor (TCR) β chain-coding genes in tumor biopsies obtained before the initiation of BRAFi and 10-14 d later. We observed an increase in the clonality of tumor-infiltrating lymphocytes in 7 of 8 patients receiving BRAFi, with a statistically significant 21\% aggregate increase in clonality. Over 80\% of individual T-cell clones detected after initiation of BRAFi treatment were new clones. Interestingly, the comparison of tumor infiltrates with clinical responses revealed that patients who had a high proportion of pre-existing dominant clones after the administration of BRAFi responded better to therapy than patients who had a low proportion of such pre-existing dominant clones following BRAFi. These data suggest that although the inhibition of BRAF in melanoma patients results in tumor infiltration by new lymphocytes, the response to treatment appears to be related to the presence of a pre-existing population of tumor-infiltrating T-cell clones.},
	issn = {2162-4011},
	doi = {10.4161/onci.26615},
	author = {Cooper, Zachary A and Frederick, Dennie T and Juneja, Vikram R and Sullivan, Ryan J and Lawrence, Donald P and Piris, Adriano and Sharpe, Arlene H and Fisher, David E and Flaherty, Keith T and Wargo, Jennifer A}
}
@article {542096,
	title = {Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality.},
	journal = {Blood},
	volume = {122},
	number = {17},
	year = {2013},
	month = {2013 Oct 24},
	pages = {3062-73},
	abstract = {Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, play an important role in the maintenance of peripheral tolerance. We explored the role of PD-1 ligands in regulating graft-versus-host disease (GVHD). Both PD-L1 and PD-L2 expression were upregulated in the spleen, liver, colon, and ileum of GVHD mice. Whereas PD-L2 expression was limited to hematopoietic cells, hematopoietic and endothelial cells expressed PD-L1. PD-1/PD-L1, but not PD-1/PD-L2, blockade markedly accelerated GVHD-induced lethality. Chimera studies suggest that PD-L1 expression on host parenchymal cells is more critical than hematopoietic cells in regulating acute GVHD. Rapid mortality onset in PD-L1-deficient hosts was associated with increased gut T-cell homing and loss of intestinal epithelial integrity, along with increased donor T-cell proliferation, activation, Th1 cytokine production, and reduced apoptosis. Bioenergetics profile analysis of proliferating alloreactive donor T-cells demonstrated increased aerobic glycolysis and oxidative phosphorylation in PD-L1-deficient hosts. Donor T-cells exhibited a hyperpolarized mitochondrial membrane potential, increased superoxide production, and increased expression of a glucose transporter in PD-L1-deficient hosts. Taken together, these data provide new insight into the differential roles of host PD-L1 and PD-L2 and their associated cellular and metabolic mechanisms controlling acute GVHD.},
	keywords = {Acute Disease, Animals, Antigens, CD274, Apoptosis Regulatory Proteins, Bone Marrow Transplantation, CD4-Positive T-Lymphocytes, Cell Proliferation, Gene Expression Regulation, Glucose Transport Proteins, Facilitative, Glycolysis, Graft vs Host Disease, Intestines, Liver, Mice, Oxidative Phosphorylation, Peripheral Tolerance, Programmed Cell Death 1 Ligand 2 Protein, Programmed Cell Death 1 Receptor, Spleen, Survival Analysis, Transplantation Tolerance},
	issn = {1528-0020},
	doi = {10.1182/blood-2013-05-500801},
	author = {Saha, Asim and Aoyama, Kazutoshi and Taylor, Patricia A and Koehn, Brent H and Veenstra, Rachelle G and Panoskaltsis-Mortari, Angela and Munn, David H and Murphy, William J and Azuma, Miyuki and Yagita, Hideo and Fife, Brian T and Sayegh, Mohammed H and Najafian, Nader and Socie, Gerard and Ahmed, Rafi and Freeman, Gordon J and Sharpe, Arlene H and Blazar, Bruce R}
}
@article {542101,
	title = {Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1).},
	journal = {Proc Natl Acad Sci U S A},
	volume = {110},
	number = {37},
	year = {2013},
	month = {2013 Sep 10},
	pages = {15001-6},
	abstract = {Hepatitis C virus (HCV) persistence is facilitated by exhaustion of CD8+ T cells that express the inhibitory receptor programmed cell death 1 (PD-1). Blockade of PD-1 signaling improves in vitro proliferation of HCV-specific T lymphocytes, but whether antiviral function can be restored in infected individuals is unknown. To address this question, chimpanzees with persistent HCV infection were treated with anti-PD-1 antibodies. A significant reduction in HCV viremia was observed in one of three treated animals without apparent hepatocellular injury. Viremia rebounded in the responder animal when antibody treatment was discontinued. Control of HCV replication was associated with restoration of intrahepatic CD4+ and CD8+ T-cell immunity against multiple HCV proteins. The responder animal had a history of broader T-cell immunity to multiple HCV proteins than the two chimpanzees that did not respond to PD-1 therapy. The results suggest that successful PD-1 blockade likely requires a critical threshold of preexisting virus-specific T cells in liver and warrants consideration of therapeutic vaccination strategies in combination with PD-1 blockade to broaden narrow responses. Anti-PD-1 immunotherapy may also facilitate control of other persistent viruses, notably the hepatitis B virus where options for long-term control of virus replication are limited.},
	keywords = {Animals, Antibodies, Monoclonal, CD8-Positive T-Lymphocytes, Disease Models, Animal, Hepacivirus, Hepatitis C, Chronic, Immunotherapy, Pan troglodytes, Programmed Cell Death 1 Receptor, Viremia, Virus Replication},
	issn = {1091-6490},
	doi = {10.1073/pnas.1312772110},
	author = {Fuller, Michael J and Callendret, Benoit and Zhu, Baogong and Freeman, Gordon J and Hasselschwert, Dana L and Satterfield, William and Sharpe, Arlene H and Dustin, Lynn B and Rice, Charles M and Grakoui, Arash and Ahmed, Rafi and Walker, Christopher M}
}
@article {542081,
	title = {PD-1 dependent exhaustion of CD8+ T cells drives chronic malaria.},
	journal = {Cell Rep},
	volume = {5},
	number = {5},
	year = {2013},
	month = {2013 Dec 12},
	pages = {1204-13},
	abstract = {Malaria is a highly prevalent disease caused by infection by Plasmodium spp., which infect hepatocytes and erythrocytes. Blood-stage infections cause devastating symptoms and can persist for years. Antibodies and CD4(+) T~cells are thought to protect against blood-stage infections. However, there has been considerable difficulty in developing an efficacious malaria vaccine, highlighting our incomplete understanding of immunity against this disease. Here, we used an experimental rodent malaria model to show that PD-1 mediates up to a 95\% reduction in numbers and functional capacity of parasite-specific CD8(+) T~cells. Furthermore, in contrast to widely held views, parasite-specific CD8(+) T~cells are required to control both acute and chronic blood-stage disease even when parasite-specific antibodies and CD4(+) T~cells are present. Our findings provide a molecular explanation for chronic malaria that will be relevant to future malaria-vaccine design and may need consideration when vaccine development for other infections is problematic.},
	keywords = {Animals, CD8-Positive T-Lymphocytes, Malaria, Mice, Mice, Inbred C57BL, Programmed Cell Death 1 Receptor},
	issn = {2211-1247},
	doi = {10.1016/j.celrep.2013.11.002},
	author = {Horne-Debets, Joshua M and Faleiro, Rebecca and Karunarathne, Deshapriya S and Liu, Xue Q and Lineburg, Katie E and Poh, Chek Meng and Grotenbreg, Gijsbert M and Hill, Geoffrey R and MacDonald, Kelli P A and Good, Michael F and Renia, Laurent and Ahmed, Rafi and Sharpe, Arlene H and Wykes, Michelle N}
}
@article {542106,
	title = {SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase.},
	journal = {Mol Cell},
	volume = {50},
	number = {5},
	year = {2013},
	month = {2013 Jun 6},
	pages = {686-98},
	abstract = {Lipid metabolism is tightly controlled by the nutritional state of the organism. Nutrient-rich conditions increase lipogenesis, whereas nutrient deprivation promotes fat oxidation. In this study, we identify the mitochondrial sirtuin, SIRT4, as a regulator of lipid homeostasis. SIRT4 is active in nutrient-replete conditions to repress fatty acid oxidation while promoting lipid anabolism. SIRT4 deacetylates and inhibits malonyl CoA decarboxylase (MCD), an enzyme that produces acetyl CoA from malonyl CoA. Malonyl CoA provides the carbon skeleton for lipogenesis and also inhibits fat oxidation. Mice lacking SIRT4 display elevated MCD activity and decreased malonyl CoA in skeletal muscle and white adipose tissue. Consequently, SIRT4 KO mice display deregulated lipid metabolism, leading to increased exercise tolerance and protection against diet-induced obesity. In sum, this work elucidates SIRT4 as an important regulator of lipid homeostasis, identifies MCD as a SIRT4 target, and deepens our understanding of the malonyl CoA regulatory axis.},
	keywords = {Acetylation, Adipose Tissue, White, Animals, Carboxy-Lyases, Diet, Fatty Acids, Lipid Metabolism, Lipids, Male, Mice, Mice, Knockout, Mitochondrial Proteins, Obesity, Oxidation-Reduction, Sirtuins},
	issn = {1097-4164},
	doi = {10.1016/j.molcel.2013.05.012},
	author = {Laurent, Ga{\"e}lle and German, Natalie J and Saha, Asish K and de Boer, Vincent C J and Davies, Michael and Koves, Timothy R and Dephoure, Noah and Fischer, Frank and Boanca, Gina and Vaitheesvaran, Bhavapriya and Lovitch, Scott B and Sharpe, Arlene H and Kurland, Irwin J and Steegborn, Clemens and Gygi, Steven P and Muoio, Deborah M and Ruderman, Neil B and Haigis, Marcia C}
}
@article {542176,
	title = {Antigen recognition is facilitated by invadosome-like protrusions formed by memory/effector T cells.},
	journal = {J Immunol},
	volume = {188},
	number = {8},
	year = {2012},
	month = {2012 Apr 15},
	pages = {3686-99},
	abstract = {Adaptive immunity requires that T cells efficiently scan diverse cell surfaces to identify cognate Ag. However, the basic cellular mechanisms remain unclear. In this study, we investigated this process using vascular endothelial cells, APCs that possess a unique and extremely advantageous, planar morphology. High-resolution imaging revealed that CD4 memory/effector T cells dynamically probe the endothelium by extending submicron-scale, actin-rich "invadosome/podosome-like protrusions" (ILPs). The intimate intercellular contacts enforced by ILPs consistently preceded and supported T cell activation in response to endothelial MHC class II/Ag. The resulting calcium flux stabilized dense arrays of ILPs (each enriched in TCR, protein kinase C-θ, ZAP70, phosphotyrosine, and HS1), forming what we term a podo-synapse. Similar findings were made using CD8 CTLs on endothelium. Furthermore, careful re-examination of both traditional APC models and professional APCs suggests broad relevance for ILPs in facilitating Ag recognition. Together, our results indicate that ILPs function as sensory organelles that serve as actuators of immune surveillance.},
	keywords = {Adaptive Immunity, Animals, Antigen Presentation, Antigen-Presenting Cells, Antigens, Bacterial, Calcium, Calcium Signaling, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Communication, Cell Surface Extensions, CHO Cells, Cricetinae, Endothelial Cells, Genes, MHC Class II, Humans, Immunologic Memory, Lymphocyte Activation, Receptors, Antigen, T-Cell, Transendothelial and Transepithelial Migration, Transfection},
	issn = {1550-6606},
	doi = {10.4049/jimmunol.1102594},
	author = {Sage, Peter T and Varghese, Laya M and Martinelli, Roberta and Tracey E Sciuto and Kamei, Masataka and Ann M Dvorak and Springer, Timothy A. and Sharpe, Arlene H and Carman, Christopher V}
}
@article {542161,
	title = {CD28 ligation increases macrophage suppression of T-cell proliferation.},
	journal = {Cell Mol Immunol},
	volume = {9},
	number = {4},
	year = {2012},
	month = {2012 Jul},
	pages = {341-9},
	abstract = {When compared to spleen or lymph node cells, resident peritoneal cavity cells respond poorly to T-cell activation in vitro. The greater proportional representation of macrophages in this cell source has been shown to actively suppress the T-cell response. Peritoneal macrophages exhibit an immature phenotype (MHC class II(lo), B7(lo)) that reduces their efficacy as antigen-presenting cells. Furthermore, these cells readily express inducible nitric oxide synthase (iNOS), an enzyme that promotes T-cell tolerance by catabolism of the limiting amino acid arginine. Here, we investigate the ability of exogenous T-cell costimulation to recover the peritoneal T-cell response. We show that CD28 ligation failed to recover the peritoneal T-cell response and actually suppressed responses that had been recovered by inhibiting iNOS. As indicated by cytokine ELISpot and neutralizing monoclonal antibody (mAb) treatment, this {\textquoteright}cosuppression{\textquoteright} response was due to CD28 ligation increasing the number of interferon (IFN)-γ-secreting cells. Our results illustrate that cellular composition and cytokine milieu influence T-cell costimulation biology.Cellular \& Molecular Immunology advance online publication, 23 April 2012; doi:10.1038/cmi.2012.13.},
	keywords = {Animals, Antigens, CD28, Cell Differentiation, Cell Proliferation, Cells, Cultured, Cellular Microenvironment, Immunosuppression, Interferon-gamma, Macrophages, Peritoneal, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Nitric Oxide Synthase Type II, Receptor Aggregation, Receptor Cross-Talk, T-Lymphocytes},
	issn = {2042-0226},
	doi = {10.1038/cmi.2012.13},
	author = {Silberman, Daniel and Bucknum, Amanda and Bartlett, Thomas and Composto, Gabriella and Kozlowski, Megan and Walker, Amanda and Werda, Amy and Cua, Jackelyn and Sharpe, Arlene H and Somerville, John E and Riggs, James E}
}
@article {542171,
	title = {CD80 expression on B cells regulates murine T follicular helper development, germinal center B cell survival, and plasma cell generation.},
	journal = {J Immunol},
	volume = {188},
	number = {9},
	year = {2012},
	month = {2012 May 1},
	pages = {4217-25},
	abstract = {Germinal center (GC) B cells and T follicular helper (T(FH)) cells interact in the production of high-affinity long-lived plasma cells (PCs) and memory B cells, although the mechanisms regulating the formation of these long-lived populations remain unclear. Because CD80 is one of the few markers shared by human and murine memory B cells, we investigated its role in the development of GCs, memory cells, and PCs. In CD80-deficient mice, fewer long-lived PCs were generated upon immunization compared with that in B6 controls. In concert, the absence of CD80 resulted in an increase in apoptotic GC B cells during the contraction phase of the GC. CD80(-/-) mice had fewer T(FH) cells compared with that of B6, and residual T(FH) cells failed to mature, with decreased ICOS and PD-1 expression and decreased synthesis of IL-21 mRNA. Mixed bone marrow chimeras demonstrated a B cell-intrinsic requirement for CD80 expression for normal T(FH) cell and PC development. Therefore, B cell expression of CD80 plays a critical role in regulating B-T interactions in both early and late GC responses. This, in turn, results in impaired ability to produce long-lived PCs. These data provide new insights into the development of GCs and Ab-forming cells and the functions of CD80 in humoral immunity.},
	keywords = {Animals, Antigens, CD80, Antigens, Differentiation, Apoptosis, Cell Survival, Cells, Cultured, Germinal Center, Humans, Immunity, Humoral, Inducible T-Cell Co-Stimulator Protein, Interleukins, Mice, Mice, Inbred BALB C, Mice, Knockout, Plasma Cells, Programmed Cell Death 1 Receptor, RNA, Messenger, T-Lymphocytes, Helper-Inducer},
	issn = {1550-6606},
	doi = {10.4049/jimmunol.1102885},
	author = {Good-Jacobson, Kim L and Song, Eunice and Anderson, Shannon and Sharpe, Arlene H and Shlomchik, Mark J}
}
@article {542181,
	title = {Interleukin-4 production by follicular helper T cells requires the conserved Il4 enhancer hypersensitivity site V.},
	journal = {Immunity},
	volume = {36},
	number = {2},
	year = {2012},
	month = {2012 Feb 24},
	pages = {175-87},
	abstract = {Follicular helper T cells (Tfh cells) are the major producers of interleukin-4 (IL-4) in secondary lymphoid organs where humoral immune responses develop. Il4 regulation in Tfh cells appears distinct from the classical T helper 2 (Th2) cell pathway, but the underlying molecular mechanisms remain largely unknown. We found that hypersensitivity site V (HS V; also known as CNS2), a 3{\textquoteright} enhancer in the Il4 locus, is essential for IL-4 production by Tfh cells. Mice lacking HS V display marked defects in type 2 humoral immune responses, as evidenced by abrogated IgE and sharply reduced IgG1 production in vivo. In contrast, effector Th2 cells that are involved in tissue responses were far less dependent on HS V. HS V facilitated removal of repressive chromatin marks during Th2 and Tfh cell differentiation and increased accessibility of the Il4 promoter. Thus, Tfh and Th2 cells utilize distinct but overlapping molecular mechanisms to regulate Il4, a finding with important implications for understanding the molecular basis of allergic diseases.},
	keywords = {Animals, Binding Sites, Conserved Sequence, Cytokines, Enhancer Elements, Genetic, Hypersensitivity, Immunity, Humoral, Interleukin-4, Lung, Mice, Mice, Inbred BALB C, Mice, Knockout, NFATC Transcription Factors, Promoter Regions, Genetic, Sequence Deletion, T-Lymphocyte Subsets, T-Lymphocytes, Helper-Inducer, Th2 Cells, Transcription, Genetic},
	issn = {1097-4180},
	doi = {10.1016/j.immuni.2011.12.014},
	author = {Vijayanand, Pandurangan and Seumois, Gr{\'e}gory and Simpson, Laura J and Abdul-Wajid, Sarah and Baumjohann, Dirk and Panduro, Marisella and Huang, Xiaozhu and Interlandi, Jeneen and Djuretic, Ivana M and Brown, Daniel R and Sharpe, Arlene H and Rao, Anjana and Ansel, K Mark}
}
@article {542186,
	title = {A new therapeutic strategy for malaria: targeting T cell exhaustion.},
	journal = {Nat Immunol},
	volume = {13},
	number = {2},
	year = {2012},
	month = {2012 Feb},
	pages = {113-5},
	keywords = {Animals, Antigens, CD, Antigens, CD274, CD4-Positive T-Lymphocytes, Female, Humans, Malaria, Falciparum, Plasmodium falciparum},
	issn = {1529-2916},
	doi = {10.1038/ni.2211},
	author = {Freeman, Gordon J and Sharpe, Arlene H}
}
@article {542196,
	title = {Overexpression of the Ctla-4 isoform lacking exons 2 and 3 causes autoimmunity.},
	journal = {J Immunol},
	volume = {188},
	number = {1},
	year = {2012},
	month = {2012 Jan 1},
	pages = {155-62},
	abstract = {CTLA-4 is a potent inhibitor of T cell activation, primarily upon binding to its costimulatory ligands (B7.1 and B7.2) expressed on APCs. However, variants of CTLA-4 can also function independently of B7 molecules. 1/4CTLA-4 is a highly conserved isoform encoded by exons 1 and 4 of the Ctla4 gene that lacks the ligand-binding and the transmembrane domains, and as yet, its function is not known. To investigate the function of 1/4CTLA-4, we generated transgenic (Tg) mice overexpressing this variant. Cytokine production by 1/4CTLA-4 Tg T cells was elevated compared with wild type T cells. The frequency of CD44(high) memory T cells in 1/4CTLA-4 Tg mice was increased, and as the mice aged, the frequency further increased. 1/4CTLA-4 Tg mice >1 y old had increased expression of T cell activation markers and developed spontaneous autoimmunity, including elevated production of autoantibodies. In contrast with young 1/4CTLA-4 Tg mice, aged 1/4CTLA-4 Tg mice had elevated frequencies of Foxp3(+) regulatory T cells, but the regulatory T cells from these mice were not able to inhibit colitis development. Collectively, these data suggest that the function of the 1/4CTLA-4 isoform is distinct from that of CTLA-4 in that it enhances T cell activation and promotes autoimmunity rather than inhibiting immune responses.},
	keywords = {Animals, Autoantibodies, Autoimmune Diseases, Autoimmunity, Colitis, CTLA-4 Antigen, Exons, Immunologic Memory, Lymphocyte Activation, Mice, Mice, Transgenic, Protein Isoforms, T-Lymphocytes, Regulatory},
	issn = {1550-6606},
	doi = {10.4049/jimmunol.1102042},
	author = {Liu, Sue M and Sutherland, Andrew P R and Zhang, Zheng and Rainbow, Daniel B and Quintana, Francisco J and Paterson, Alison M and Sharpe, Arlene H and Oukka, Mohamed and Wicker, Linda S and Kuchroo, Vijay K}
}
@article {542166,
	title = {PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis.},
	journal = {J Immunol},
	volume = {188},
	number = {10},
	year = {2012},
	month = {2012 May 15},
	pages = {4876-84},
	abstract = {PD-1, a member of the CD28 family of immune regulatory molecules, is expressed on activated T cells, interacts with its ligands, PD-L1/B7-H1 and PD-L2/B7-DC, on other cells, and delivers inhibitory signals to the T cell. We studied the role of this pathway in modulating autoreactive T cell responses in two models of myocarditis. In a CD8(+) T cell-mediated adoptive transfer model, we found that compared with Pd1(+/+) CD8(+) T cells, Pd1(-/-) CD8(+) T cells cause enhanced disease, with increased inflammatory infiltrate, particularly rich in neutrophils. Additionally, we show enhanced proliferation in vivo and enhanced cytotoxic activity of PD-1-deficient T lymphocytes against myocardial endothelial cells in vitro. In experimental autoimmune myocarditis, a disease model dependent on CD4(+) T cells, we show that mice lacking PD-1 develop enhanced disease compared with wild-type mice. PD-1-deficient mice displayed increased inflammation, enhanced serum markers of myocardial damage, and an increased infiltration of inflammatory cells, including CD8(+) T cells. Together, these studies show that PD-1 plays an important role in limiting T cell responses in the heart.},
	keywords = {Amino Acid Sequence, Animals, Cell Movement, Cells, Cultured, Coculture Techniques, Disease Models, Animal, Female, Inflammation, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Molecular Sequence Data, Muscle Cells, Myocarditis, Programmed Cell Death 1 Receptor, T-Lymphocyte Subsets},
	issn = {1550-6606},
	doi = {10.4049/jimmunol.1200389},
	author = {Tarrio, Margarite L and Grabie, Nir and Bu, De-xiu and Sharpe, Arlene H and Lichtman, Andrew H}
}
@article {542146,
	title = {CD28 costimulation regulates genome-wide effects on alternative splicing.},
	journal = {PLoS One},
	volume = {7},
	number = {6},
	year = {2012},
	month = {2012},
	pages = {e40032},
	abstract = {CD28 is the major costimulatory receptor required for activation of na{\"\i}ve T cells, yet CD28 costimulation affects the expression level of surprisingly few genes over those altered by TCR stimulation alone. Alternate splicing of genes adds diversity to the proteome and contributes to tissue-specific regulation of genes. Here we demonstrate that CD28 costimulation leads to major changes in alternative splicing during activation of na{\"\i}ve T cells, beyond the effects of TCR alone. CD28 costimulation affected many more genes through modulation of alternate splicing than by modulation of transcription. Different families of biological processes are over-represented among genes alternatively spliced in response to CD28 costimulation compared to those genes whose transcription is altered, suggesting that alternative splicing regulates distinct biological effects. Moreover, genes dependent upon hnRNPLL, a global regulator of splicing in activated T cells, were enriched in T cells activated through TCR plus CD28 as compared to TCR alone. We show that hnRNPLL expression is dependent on CD28 signaling, providing a mechanism by which CD28 can regulate splicing in T cells and insight into how hnRNPLL can influence signal-induced alternative splicing in T cells. The effects of CD28 on alternative splicing provide a newly appreciated means by which CD28 can regulate T cell responses.},
	keywords = {Alternative Splicing, Animals, Antigens, CD28, Antigens, Differentiation, T-Lymphocyte, CD4-Positive T-Lymphocytes, Down-Regulation, Gene Expression Profiling, Genome, Heterogeneous-Nuclear Ribonucleoproteins, Interleukin-3, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Receptors, Antigen, T-Cell, Receptors, CCR, RNA, Messenger, Signal Transduction, Transcription, Genetic, Up-Regulation},
	issn = {1932-6203},
	doi = {10.1371/journal.pone.0040032},
	author = {Butte, Manish J and Lee, Sun Jung and Jesneck, Jonathan and Keir, Mary E and Haining, W Nicholas and Sharpe, Arlene H}
}
@article {542151,
	title = {Interleukin-27 priming of T cells controls IL-17 production in trans via induction of the ligand PD-L1.},
	journal = {Immunity},
	volume = {36},
	number = {6},
	year = {2012},
	month = {2012 Jun 29},
	pages = {1017-30},
	abstract = {Interleukin-27 (IL-27) is a key immunosuppressive cytokine that counters T helper 17 (Th17) cell-mediated pathology. To identify mechanisms by which IL-27 might exert its immunosuppressive effect, we analyzed genes in T~cells rapidly induced by IL-27. We found that IL-27 priming of naive T~cells upregulated expression of programmed death ligand 1 (PD-L1) in a signal transducer and activator of transcription 1 (STAT1)-dependent manner. When cocultured with naive CD4(+) T~cells, IL-27-primed T~cells inhibited the differentiation of Th17 cells in trans through~a PD-1-PD-L1 interaction. In~vivo, coadministration of~naive TCR transgenic T~cells (2D2 T~cells) with IL-27-primed T~cells expressing PD-L1 inhibited the~development of Th17 cells and protected from severe autoimmune encephalomyelitis. Thus, these data identify a suppressive activity of IL-27, by which CD4(+) T~cells can restrict differentiation of Th17 cells in trans.},
	keywords = {Animals, Antigens, CD274, Bystander Effect, CD4-Positive T-Lymphocytes, Cell Differentiation, Encephalomyelitis, Autoimmune, Experimental, Forkhead Transcription Factors, Gene Expression Regulation, Interferon-gamma, Interleukin-17, Interleukin-1beta, Interleukin-23, Interleukin-6, Interleukins, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Myelin Proteins, Myelin-Oligodendrocyte Glycoprotein, Receptors, Cytokine, T-Lymphocyte Subsets, Th17 Cells, Transforming Growth Factor beta},
	issn = {1097-4180},
	doi = {10.1016/j.immuni.2012.03.024},
	author = {Hirahara, Kiyoshi and Ghoreschi, Kamran and Yang, Xiang-Ping and Takahashi, Hayato and Laurence, Arian and Vahedi, Golnaz and Scium{\`e}, Giuseppe and Hall, Aisling O{\textquoteright}Hara and Dupont, Christopher D and Francisco, Loise M and Chen, Qian and Tanaka, Masao and Kanno, Yuka and Sun, Hong-Wei and Sharpe, Arlene H and Hunter, Christopher A and O{\textquoteright}Shea, John J}
}
@article {542156,
	title = {Neuronal programmed cell death-1 ligand expression regulates retinal ganglion cell number in neonatal and adult mice.},
	journal = {J Neuroophthalmol},
	volume = {32},
	number = {3},
	year = {2012},
	month = {2012 Sep},
	pages = {227-37},
	abstract = {OBJECTIVES: During mouse retina maturation, the final number of retinal ganglion cells (RGCs) is determined by highly regulated programmed cell death. Previous studies demonstrated that the immunoregulatory receptor programmed cell death-1 (PD-1) promotes developmental RGC death. To identify the functional signaling partner(s) for PD-1, we identified retinal expression of PD-1 ligands and examined the effect of PD-1 ligand expression on RGC number. We also explored the hypothesis that PD-1 signaling promotes the development of functional visual circuitry.

METHODS: Characterization of retinal and brain programmed cell death-1 ligand 1 (PD-L1) expression were examined by immunofluorescence on tissue sections. The contribution of PD-ligands, PD-L1, and programmed cell death-1 ligand 2 (PD-L2) to RGC number was examined in PD-ligand knockout mice lacking 1 or both ligands. Retinal architecture was assessed by spectral-domain optical coherence tomography, and retinal function was analyzed by electroretinography in wild-type and PD-L1/L2 double-deficient mice.

RESULTS: PD-L1 expression is found throughout the neonatal retina and persists in adult RGCs, bipolar interneurons, and M{\"u}ller glia. In the absence of both PD-ligands, there is a significant numerical increase in RGCs (34\% at postnatal day 2 [P2] and 18\% in adult), as compared to wild type, and PD-ligands have redundant function in this process. Despite the increased RGC number, adult PD-L1/L2 double-knockout mice have normal retinal architecture and outer retina function.

CONCLUSION: This study demonstrates that PD-L1 and PD-L2 together impact the final number of RGCs in adult mice and supports a novel role for active promotion of neuronal cell death through PD-1 receptor-ligand engagement.},
	keywords = {Aging, Animals, Antigens, CD274, Axons, Electroretinography, Mice, Mice, Inbred C57BL, Mice, Knockout, Optic Nerve, Programmed Cell Death 1 Ligand 2 Protein, Programmed Cell Death 1 Receptor, Retina, Retinal Ganglion Cells, Spectrum Analysis},
	issn = {1536-5166},
	doi = {10.1097/WNO.0b013e3182589589},
	author = {Sham, Caroline W and Chan, Ann M and Kwong, Jacky M K and Caprioli, Joseph and Nusinowitz, Steven and Chen, Bryan and Lee, Janice G and Gandhi, Nishant M and Francisco, Loise M and Sharpe, Arlene H and Chen, Ling and Braun, Jonathan and Gordon, Lynn K}
}
@article {542141,
	title = {Role of the PD-1 pathway in the immune response.},
	journal = {Am J Transplant},
	volume = {12},
	number = {10},
	year = {2012},
	month = {2012 Oct},
	pages = {2575-87},
	abstract = {Understanding immunoregulatory mechanisms is essential for the development of novel interventions to improve long-term allograft survival. Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, have emerged as critical inhibitory signaling pathways that regulate T cell response and maintain peripheral tolerance. PD-1 signaling inhibits alloreactive T cell activation, and can promote induced regulatory T cell development. Furthermore, the upregulation of PD-L1 on nonhematopoietic cells of the allograft may actively participate in the inhibition of immune responses and provide tissue-specific protection. In murine transplant models, this pathway has been shown to be critical for the induction and maintenance of graft tolerance. In this review, we discuss the current knowledge of the immunoregulatory functions of PD-1 and its ligands and their therapeutic potential in transplantation.},
	keywords = {Graft Survival, Humans, Immune Tolerance, Lymphocyte Activation, Organ Transplantation, Programmed Cell Death 1 Receptor, Signal Transduction, T-Lymphocytes, Regulatory},
	issn = {1600-6143},
	doi = {10.1111/j.1600-6143.2012.04224.x},
	author = {Riella, L V and Paterson, A M and Sharpe, A. H. and Chandraker, A}
}
@article {542266,
	title = {CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition.},
	journal = {J Immunol},
	volume = {186},
	number = {3},
	year = {2011},
	month = {2011 Feb 1},
	pages = {1598-607},
	abstract = {Although CD4 T cells are required for host resistance to Mycobacterium tuberculosis, they may also contribute to pathology. In this study, we examine the role of the inhibitory receptor PD-1 and its ligand PD-L1 during M. tuberculosis infection. After aerosol exposure, PD-1 knockout (KO) mice develop high numbers of M. tuberculosis-specific CD4 T cells but display markedly increased susceptibility to infection. Importantly, we show that CD4 T cells themselves drive the increased bacterial loads and pathology seen in infected PD-1 KO mice, and PD-1 deficiency in CD4 T cells is sufficient to trigger early mortality. PD-L1 KO mice also display enhanced albeit less severe susceptibility, indicating that T cells are regulated by multiple PD ligands during M. tuberculosis infection. M. tuberculosis-specific CD8 T cell responses were normal in PD-1 KO mice, and CD8 T cells only had a minor contribution to the exacerbated disease in the M. tuberculosis-infected PD-1 KO and PD-L1 KO mice. Thus, in the absence of the PD-1 pathway, M. tuberculosis benefits from CD4 T cell responses, and host resistance requires inhibition by PD-1 to prevent T cell-driven exacerbation of the infection.},
	keywords = {Aerosols, Animals, Antigens, CD274, Antigens, CD80, Antigens, Surface, Apoptosis Regulatory Proteins, CD4 Lymphocyte Count, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Epitopes, T-Lymphocyte, Genetic Predisposition to Disease, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Mycobacterium tuberculosis, Necrosis, Peptides, Programmed Cell Death 1 Receptor, Tuberculosis, Pulmonary},
	issn = {1550-6606},
	doi = {10.4049/jimmunol.1003304},
	author = {Barber, Daniel L and Mayer-Barber, Katrin D and Feng, Carl G and Sharpe, Arlene H and Sher, Alan}
}
@article {542261,
	title = {Cutting edge: TIGIT has T cell-intrinsic inhibitory functions.},
	journal = {J Immunol},
	volume = {186},
	number = {3},
	year = {2011},
	month = {2011 Feb 1},
	pages = {1338-42},
	abstract = {Costimulatory molecules regulate the functional outcome of T cell activation, and disturbance of the balance between activating and inhibitory signals results in increased susceptibility to infection or the induction of autoimmunity. Similar to the well-characterized CD28/CTLA-4 costimulatory pathway, a newly emerging pathway consisting of CD226 and T cell Ig and ITIM domain (TIGIT) has been associated with susceptibility to multiple autoimmune diseases. In this study, we examined the role of the putative coinhibitory molecule TIGIT and show that loss of TIGIT in mice results in hyperproliferative T cell responses and increased susceptibility to autoimmunity. TIGIT is thought to indirectly inhibit T cell responses by the induction of tolerogenic dendritic cells. By generating an agonistic anti-TIGIT Ab, we demonstrate that TIGIT can inhibit T cell responses directly independent of APCs. Microarray analysis of T cells stimulated with agonistic anti-TIGIT Ab revealed that TIGIT can act directly on T cells by attenuating TCR-driven activation signals.},
	keywords = {Amino Acid Sequence, Animals, Cell Proliferation, Cells, Cultured, Cricetinae, Cricetulus, Down-Regulation, Encephalomyelitis, Autoimmune, Experimental, Genetic Predisposition to Disease, Growth Inhibitors, Immunosuppressive Agents, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Molecular Sequence Data, Receptors, Immunologic, Signal Transduction, T-Lymphocytes},
	issn = {1550-6606},
	doi = {10.4049/jimmunol.1003081},
	author = {Joller, Nicole and Hafler, Jason P and Brynedal, Boel and Kassam, Nasim and Spoerl, Silvia and Levin, Steven D and Sharpe, Arlene H and Kuchroo, Vijay K}
}
@article {542231,
	title = {Anti-CD3 mAb treatment cures PDL1-/-.NOD mice of diabetes but precipitates fatal myocarditis.},
	journal = {Clin Immunol},
	volume = {140},
	number = {1},
	year = {2011},
	month = {2011 Jul},
	pages = {47-53},
	abstract = {Anti-CD3 mAb is an effective therapy that can reverse diabetes in NOD mice and has therapeutic potential in patients with type 1 diabetes (T1D). We administered anti-CD3 to PDL1-/-.NOD mice in order to determine whether this treatment would reverse the development of diabetes in these mice. Mice injected with anti-CD3 mAb neonatally were protected from T1D. However, all of these anti-CD3 mAb treated PDL1-/-.NOD mice developed a wasting disease between 12 and 20 weeks of age with sudden deterioration and weight loss, leading to death within 3-5 days of development of illness. Histology revealed severe inflammation in the heart and skeletal muscles. These results suggest that deficiency of PDL1 in NOD background has the potential to lead to immune-mediated tissue damage in organs other than the pancreas, but this cannot be appreciated in PDL1-/-.NOD mice as the mice develop T1D at an early age and die from diabetes prior to manifesting other autoimmune diseases.},
	keywords = {Animals, Antibodies, Monoclonal, Antigens, CD3, Cell Separation, Diabetes Mellitus, Type 1, Flow Cytometry, Immunologic Factors, Mice, Mice, Inbred NOD, Mice, Knockout, Myocarditis},
	issn = {1521-7035},
	doi = {10.1016/j.clim.2011.03.011},
	author = {Mfarrej, Bechara and Keir, Mary and Dada, Shirine and Trikudanathan, Subbulaxmi and Sayegh, Mohamed H and Sharpe, Arlene H and Guleria, Indira}
}
@article {542256,
	title = {Auto-antibody production and glomerulonephritis in congenic Slamf1-/- and Slamf2-/- [B6.129] but not in Slamf1-/- and Slamf2-/- [BALB/c.129] mice.},
	journal = {Int Immunol},
	volume = {23},
	number = {2},
	year = {2011},
	month = {2011 Feb},
	pages = {149-58},
	abstract = {Several genes in an interval of human and mouse chromosome 1 are associated with a predisposition for systemic lupus erythematosus. Congenic mouse strains that contain a 129-derived genomic segment, which is embedded in the B6 genome, develop lupus because of epistatic interactions between the 129-derived and B6 genes, e.g. in B6.129chr1b mice. If a gene that is located on chromosome 1 is altered through homologous recombination in 129-derived embryonic stem cells (ES cells) and if the resultant knockout mouse is backcrossed with B6, interpretation of the phenotype of the mutant mouse may be affected by epistatic interactions between the 129 and B6 genomes. Here, we report that knockout mice of two adjacent chromosome 1 genes, Slamf1(-/-) and Slamf2(-/-), which were generated with the same 129-derived ES cell line, develop features of lupus, if backcrossed on to the B6 genetic background. By contrast, Slamf1(-/-) [BALB/c.129] and Slamf2(-/-) [BALB/c.129] do not develop disease. Surprisingly, Slamf1(-/-) [B6.129] mice develop both auto-antibodies and glomerulonephritis between 3 and 6 months of age, while disease fully develops in Slamf1(-/-) [B6.129] mice after 9-14 months. Functional analyses of CD4(+) T cells reveals that Slamf2(-/-) T cells are resistant to tolerance induction in vivo. We conclude that the Slamf2(-/-) mutation may have a unique influence on T-cell tolerance and lupus.},
	keywords = {Animals, Antigens, CD, Autoantibodies, Glomerulonephritis, Humans, Immunohistochemistry, Inbreeding, Lupus Erythematosus, Systemic, Mice, Mice, 129 Strain, Mice, Congenic, Mice, Knockout, Receptors, Cell Surface},
	issn = {1460-2377},
	doi = {10.1093/intimm/dxq465},
	author = {Keszei, Marton and Latchman, Yvette E and Vanguri, Vijay K and Brown, Daniel R and Detre, Cynthia and Morra, Massimo and Arancibia-Carcamo, Carolina V and Arancibia, Carolina V and Paul, Elahna and Calpe, Silvia and Castro, Wilson and Wang, Ninghai and Terhorst, Cox and Sharpe, Arlene H}
}
@article {542221,
	title = {Cutting edge: an NK cell-independent role for Slamf4 in controlling humoral autoimmunity.},
	journal = {J Immunol},
	volume = {187},
	number = {1},
	year = {2011},
	month = {2011 Jul 1},
	pages = {21-5},
	abstract = {Several genes within a syntenic region of human and mouse chromosome 1 are associated with predisposition to systemic lupus erythematosus. Analyses of lupus-prone congenic mice have pointed to an important role for the signaling lymphocyte activation molecule family (slamf)6 surface receptor in lupus pathogenesis. In this article, we demonstrate that a second member of the Slamf gene family, Slamf4 (Cd244), contributes to lupus-related autoimmunity. B6.Slamf4(-/-) mice spontaneously develop activated CD4 T cells and B cells and increased numbers of T follicular helper cells and a proportion develop autoantibodies to nuclear Ags. B6.Slamf4(-/-) mice also exhibit markedly increased autoantibody production in the B6.C-H-2bm12/KhEg {\textrightarrow} B6 transfer model of lupus. Although slamf4 function is best characterized in NK cells, the enhanced humoral autoimmunity of B6.Slamf4(-/-) mice is NK cell independent, as judged by depletion studies. Taken together, our findings reveal that slamf4 has an NK cell-independent negative regulatory role in the pathogenesis of lupus a normally non-autoimmune prone genetic background.},
	keywords = {Animals, Antigens, CD, Autoantibodies, Chromatin, Chronic Disease, Disease Models, Animal, Genetic Predisposition to Disease, Graft vs Host Disease, Humans, Immune Tolerance, Killer Cells, Natural, Lupus Erythematosus, Systemic, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, Immunologic},
	issn = {1550-6606},
	doi = {10.4049/jimmunol.1100510},
	author = {Brown, Daniel R and Calpe, Silvia and Keszei, Marton and Wang, Ninghai and McArdel, Shannon and Terhorst, Cox and Sharpe, Arlene H}
}
@article {542241,
	title = {Essential role of PDL1 expression on nonhematopoietic donor cells in acquired tolerance to vascularized cardiac allografts.},
	journal = {Am J Transplant},
	volume = {11},
	number = {4},
	year = {2011},
	month = {2011 Apr},
	pages = {832-40},
	abstract = {The PD1:PDL1 pathway is an essential negative costimulatory pathway that plays a key role in regulating the alloimune response. PDL1 is expressed not only on antigen-presenting cells (APCs) but also cardiac endothelium. In this study, we investigated the importance of PDL1 expression on donor cardiac allograft in acquired transplantation tolerance in a fully MHC-mismatched model. We generated PDL1 chimeric mice on B6 background that expressed PDL1 on either hematopoietic cells or nonhematopoietic cells of the heart. Sham animals were used as controls. These hearts were then transplanted into BALB/c recipients and treated with CTLA4-Ig to induce tolerance. Cardiac endothelium showed significant expression of PDL1, which was upregulated upon transplantation. While the absence of PDL1 on hematopoietic cells of the heart resulted in delayed rejection and prevented long-term tolerance in most but not all recipients, we observed an accelerated and early graft rejection of all donor allografts that lacked PDL1 on the endothelium. Moreover, PDL1-deficient endothelium hearts had significant higher frequency of IFN-γ-producing alloreactive cells as well as higher frequency of CD8(+) effector T cells. These findings demonstrate that PDL1 expression mainly on donor endothelium is functionally important in a fully allogeneic mismatched model for the induction of cardiac allograft tolerance.},
	keywords = {Animals, Antigens, CD274, Antigens, CD80, Bone Marrow, Endothelium, Vascular, Flow Cytometry, Fluorescent Antibody Technique, Graft Rejection, Heart Transplantation, Hematopoietic Stem Cells, Immunoenzyme Techniques, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Peptides, Transplantation Tolerance, Transplantation, Homologous},
	issn = {1600-6143},
	doi = {10.1111/j.1600-6143.2011.03451.x},
	author = {Riella, L V and Watanabe, T and Sage, P. T. and Yang, J and Yeung, M and Azzi, J and Vanguri, V and Chandraker, A and Sharpe, A. H. and Sayegh, M H and Najafian, N}
}
@article {542246,
	title = {Impairment of the programmed cell death-1 pathway increases atherosclerotic lesion development and inflammation.},
	journal = {Arterioscler Thromb Vasc Biol},
	volume = {31},
	number = {5},
	year = {2011},
	month = {2011 May},
	pages = {1100-7},
	abstract = {OBJECTIVE: Programmed cell death-1 (PD-1) is a member of the CD28 superfamily that delivers negative signals on interaction with its 2 ligands, PD-L1 and PD-L2. We studied the contribution of the PD-1 pathway to regulation of T cells that promote atherosclerotic lesion formation and inflammation.

METHODS AND RESULTS: We show that compared with Ldlr-/- control mice, Pd1-/-Ldlr-/- mice developed larger lesions with more abundant CD4+ and CD8+ T cells and macrophages, accompanied by higher levels of serum tumor necrosis factor-α. Iliac lymph node T cells from Pd1-/-Ldlr-/- mice proliferated more to αCD3 or oxidized low-density lipoprotein stimulation compared with controls. CD8+ T cells from Pd1-/-Ldlr-/- mice displayed more cytotoxic activity compared with controls in vivo and in vitro. Administration of a blocking anti-PD-1 antibody increased lesional inflammation in hypercholesterolemic Ldlr-/- mice with more lesional T cells and more activated T cells in paraaortic lymph nodes. The changes in lesional T-cell content when PD-1 was absent or blocked were also observed in bone marrow chimeric Ldlr-/- mice lacking PD-L1 and PD-L2 on hematopoietic cells.

CONCLUSIONS: PD-1 has an important role in downregulating proatherogenic T-cell responses, and blockade of this molecule for treatment of viral infections or cancer may increase risk of cardiovascular complications.},
	keywords = {Animals, Antibodies, Blocking, Antigens, CD274, Antigens, CD3, Antigens, CD80, Antigens, Surface, Apoptosis, Apoptosis Regulatory Proteins, Atherosclerosis, Bone Marrow Transplantation, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Proliferation, Cells, Cultured, Disease Models, Animal, Genes, T-Cell Receptor, Genotype, Hypercholesterolemia, Inflammation, Lipoproteins, LDL, Lymph Nodes, Lymphocyte Activation, Macrophages, Male, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Peptides, Phenotype, Programmed Cell Death 1 Ligand 2 Protein, Programmed Cell Death 1 Receptor, Receptors, LDL, Signal Transduction, T-Lymphocyte Subsets, T-Lymphocytes, Cytotoxic, Time Factors, Tumor Necrosis Factor-alpha},
	issn = {1524-4636},
	doi = {10.1161/ATVBAHA.111.224709},
	author = {Bu, De-xiu and Tarrio, Margarite and Maganto-Garcia, Elena and Stavrakis, George and Tajima, Goro and Lederer, James and Jarolim, Petr and Freeman, Gordon J and Sharpe, Arlene H and Lichtman, Andrew H}
}
@article {542216,
	title = {The novel costimulatory programmed death ligand 1/B7.1 pathway is functional in inhibiting alloimmune responses in vivo.},
	journal = {J Immunol},
	volume = {187},
	number = {3},
	year = {2011},
	month = {2011 Aug 1},
	pages = {1113-9},
	abstract = {The programmed death ligand 1 (PDL1)/programmed death 1 (PD1) costimulatory pathway plays an important role in the inhibition of alloimmune responses as well as in the induction and maintenance of peripheral tolerance. It has been demonstrated recently that PDL1 also can bind B7.1 to inhibit T cell responses in vitro. Using the bm12 into B6 heart transplant model, we investigated the functional significance of this interaction in alloimmune responses in vivo. PD1 blockade unlike PDL1 blockade failed to accelerate bm12 allograft rejection, suggesting a role for an additional binding partner for PDL1 other than PD1 in transplant rejection. PDL1 blockade was able to accelerate allograft rejection in B7.2-deficient recipients but not B7.1-deficient recipients, indicating that PDL1 interaction with B7.1 was important in inhibiting rejection. Administration of the novel 2H11 anti-PDL1 mAb, which only blocks the PDL1-B7.1 interaction, aggravated chronic injury of bm12 allografts in B6 recipients. Aggravated chronic injury was associated with an increased frequency of alloreactive IFN-γ-, IL-4-, and IL-6-producing splenocytes and a decreased percentage of regulatory T cells in the recipients. Using an in vitro cell culture assay, blockade of the interaction of PDL1 on dendritic cells with B7.1 on T cells increased IFN-γ production from alloreactive CD4(+) T cells, whereas blockade of dendritic cell B7.1 interaction with T cell PDL1 did not. These data indicate that PDL1 interaction with B7.1 plays an important role in the inhibition of alloimmune responses in vivo and suggests a dominant direction for PDL1 and B7.1 interaction.},
	keywords = {Animals, Antigen-Presenting Cells, Antigens, CD, Antigens, CD80, Apoptosis Regulatory Proteins, Cells, Cultured, Graft Survival, Heart Transplantation, Ligands, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Programmed Cell Death 1 Receptor, Self Tolerance, Signal Transduction, Skin Transplantation},
	issn = {1550-6606},
	doi = {10.4049/jimmunol.1100056},
	author = {Yang, Jun and Riella, Leonardo V and Chock, Susanne and Liu, Tao and Zhao, Xiaozhi and Yuan, Xueli and Paterson, Alison M and Watanabe, Toshihiko and Vanguri, Vijay and Yagita, Hideo and Azuma, Miyuki and Blazar, Bruce R and Freeman, Gordon J and Rodig, Scott J and Sharpe, Arlene H and Chandraker, Anil and Sayegh, Mohamed H}
}
@article {542236,
	title = {A novel function for programmed death ligand-1 regulation of angiogenesis.},
	journal = {Am J Pathol},
	volume = {178},
	number = {4},
	year = {2011},
	month = {2011 Apr},
	pages = {1922-9},
	abstract = {Programmed death ligand-1 (PD-L1) plays a critical role in T-cell regulatory function. Here, we report a newly discovered effect of PD-L1 on angiogenesis. We demonstrate that PD-L1 and its receptor CD80, but not PD-1, are expressed by primary murine lung and heart vascular endothelial cells and the miscrovascular endothelial cell line (MS1) at both the mRNA and protein levels in vitro. The inhibition of PD-L1 or CD80 expression in MS1 cells, by small-interfering RNA transfection, led to a significant up-regulation of vascular endothelial growth factor receptor 2 expression and cell proliferation levels in MS1 cells. Furthermore, MS1 cells were found to have a significantly lower proliferation and vascular endothelial growth factor receptor 2 expression levels when they were co-cultured with PD-L1-expressing normal corneal epithelial cells, as compared to MS1 cells co-cultured with PD-L1(-/-) corneal epithelial cells. In a suture-induced corneal angiogenesis model, we observed a significantly higher level of angiogenic response in PD-L1(-/-) knockout mice as compared to wild-type mice, although there was no significant difference in the expression of inflammatory cytokines (interleukin-1α, interleukin-1β, or tumor necrosis factor-α) or the infiltration of innate immune cells (neutrophils and macrophages) between the two groups. We conclude that the expression of PD-L1 in both vascular endothelial cells and corneal epithelial cells regulates corneal angiogenesis.},
	keywords = {Animals, Antigens, CD274, Antigens, CD80, Cornea, Endothelial Cells, Gene Expression Regulation, Inflammation, Interleukin-1alpha, Interleukin-1beta, Lung, Male, Membrane Glycoproteins, Mice, Mice, Knockout, Microcirculation, Myocardium, Neovascularization, Pathologic, Peptides},
	issn = {1525-2191},
	doi = {10.1016/j.ajpath.2010.12.027},
	author = {Jin, Yiping and Chauhan, Sunil K and El Annan, Jaafar and Annan, Jaafar E I and Sage, Peter T and Sharpe, Arlene H and Dana, Reza}
}
@article {542211,
	title = {The programmed death-1 ligand 1:B7-1 pathway restrains diabetogenic effector T cells in vivo.},
	journal = {J Immunol},
	volume = {187},
	number = {3},
	year = {2011},
	month = {2011 Aug 1},
	pages = {1097-105},
	abstract = {Programmed death-1 ligand 1 (PD-L1) is a coinhibitory molecule that negatively regulates multiple tolerance checkpoints. In the NOD mouse model, PD-L1 regulates the development of diabetes. PD-L1 has two binding partners, programmed death-1 and B7-1, but the significance of the PD-L1:B7-1 interaction in regulating self-reactive T cell responses is not yet clear. To investigate this issue in NOD mice, we have compared the effects of two anti-PD-L1 Abs that have different blocking activities. Anti-PD-L1 mAb 10F.2H11 sterically and functionally blocks only PD-L1:B7-1 interactions, whereas anti-PD-L1 mAb 10F.9G2 blocks both PD-L1:B7-1 and PD-L1:programmed death-1 interactions. Both Abs had potent, yet distinct effects in accelerating diabetes in NOD mice: the single-blocker 10F.2H11 mAb was more effective at precipitating diabetes in older (13-wk-old) than in younger (6- to 7-wk-old) mice, whereas the dual-blocker 10F.9G2 mAb rapidly induced diabetes in NOD mice of both ages. Similarly, 10F.2H11 accelerated diabetes in recipients of T cells from diabetic, but not prediabetic mice, whereas 10F.9G2 was effective in both settings. Both anti-PD-L1 mAbs precipitated diabetes in adoptive transfer models of CD4(+) and CD8(+) T cell-driven diabetes. Taken together, these data demonstrate that the PD-L1:B7-1 pathway inhibits potentially pathogenic self-reactive effector CD4(+) and CD8(+) T cell responses in vivo, and suggest that the immunoinhibitory functions of this pathway may be particularly important during the later phases of diabetogenesis.},
	keywords = {Adoptive Transfer, Animals, Antibodies, Blocking, Antigens, CD, Antigens, CD274, Antigens, CD80, Apoptosis Regulatory Proteins, Autoimmune Diseases, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Diabetes Mellitus, Type 1, Female, Growth Inhibitors, Ligands, Membrane Glycoproteins, Mice, Mice, Inbred NOD, Mice, SCID, Mice, Transgenic, Peptides, Programmed Cell Death 1 Receptor, Protein Binding, Signal Transduction},
	issn = {1550-6606},
	doi = {10.4049/jimmunol.1003496},
	author = {Paterson, Alison M and Brown, Keturah E and Keir, Mary E and Vanguri, Vijay K and Riella, Leonardo V and Chandraker, Anil and Sayegh, Mohamed H and Blazar, Bruce R and Freeman, Gordon J and Sharpe, Arlene H}
}
@article {542251,
	title = {The role of LAT in increased CD8+ T cell exhaustion in trigeminal ganglia of mice latently infected with herpes simplex virus 1.},
	journal = {J Virol},
	volume = {85},
	number = {9},
	year = {2011},
	month = {2011 May},
	pages = {4184-97},
	abstract = {Herpes simplex virus (HSV) infection is a classic example of latent viral infection in humans and experimental animal models. The HSV-1 latency-associated transcript (LAT) plays a major role in the HSV-1 latency reactivation cycle and thus in recurrent disease. Whether the presence of LAT leads to generation of dysfunctional T cell responses in the trigeminal ganglia (TG) of latently infected mice is not known. To address this issue, we used LAT-positive [LAT(+)] and LAT-deficient [LAT(-)] viruses to evaluate the effect of LAT on CD8 T cell exhaustion in TG of latently infected mice. The amount of latency as determined by quantitative reverse transcription-PCR (qRT-PCR) of viral DNA in total TG extracts was 3-fold higher with LAT(+) than with LAT(-) virus. LAT expression and increased latency correlated with increased mRNA levels of CD8, PD-1, and Tim-3. PD-1 is both a marker for exhaustion and a primary factor leading to exhaustion, and Tim-3 can also contribute to exhaustion. These results suggested that LAT(+) TG contain both more CD8(+) T cells and more CD8(+) T cells expressing the exhaustion markers PD-1 and Tim-3. This was confirmed by flow cytometry analyses of expression of CD3/CD8/PD-1/Tim-3, HSV-1, CD8(+) T cell pentamer (specific for a peptide derived from residues 498 to 505 of glycoprotein B [gB(498-505)]), interleukin-2 (IL-2), and tumor necrosis factor alpha (TNF-α). The functional significance of PD-1 and its ligands in HSV-1 latency was demonstrated by the significantly reduced amount of HSV-1 latency in PD-1- and PD-L1-deficient mice. Together, these results may suggest that both PD-1 and Tim-3 are mediators of CD8(+) T cell exhaustion and latency in HSV-1 infection.},
	keywords = {Animals, Antigens, CD8, Antigens, Differentiation, CD8-Positive T-Lymphocytes, Flow Cytometry, Gene Expression Profiling, Herpes Simplex, Herpesvirus 1, Human, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, MicroRNAs, Programmed Cell Death 1 Receptor, Receptors, Virus, Trigeminal Ganglion, Virus Latency},
	issn = {1098-5514},
	doi = {10.1128/JVI.02290-10},
	author = {Allen, Sariah J and Hamrah, Pedram and Gate, David and Mott, Kevin R and Mantopoulos, Dimosthenis and Zheng, Lixin and Town, Terrence and Jones, Clinton and von Andrian, Ulrich H and Freeman, Gordon J and Sharpe, Arlene H and BenMohamed, Lbachir and Ahmed, Rafi and Wechsler, Steven L and Ghiasi, Homayon}
}
@article {542226,
	title = {The SLAM family member CD48 (Slamf2) protects lupus-prone mice from autoimmune nephritis.},
	journal = {J Autoimmun},
	volume = {37},
	number = {1},
	year = {2011},
	month = {2011 Aug},
	pages = {48-57},
	abstract = {Polymorphisms in the SLAM family of leukocyte cell surface regulatory molecules have been associated with lupus-like phenotypes in both humans and mice. The murine Slamf gene cluster lies within the lupus-associated Sle1b region of mouse chromosome 1. Non-autoreactive C57BL/6 (B6) mice that have had this region replaced by syntenic segments from other mouse strains (i.e. 129, NZB and NZW) are B6 congenic strains that spontaneously produce non-nephritogenic lupus-like autoantibodies. We have recently reported that genetic ablation of the SLAM family member CD48 (Slamf2) drives full-blown autoimmune disease with severe proliferative glomerulonephritis (CD48GN) in B6 mice carrying 129 sequences of the Sle1b region (B6.129CD48(-/-)). We also discovered that BALB/c mice with the same 129-derived CD48-null allele (BALB.129CD48(-/-)) have neither nephritis nor anti-DNA autoantibodies, indicating that strain specific background genes modulate the effects of CD48 deficiency. Here we further examine this novel model of lupus nephritis in which CD48 deficiency transforms benign autoreactivity into fatal nephritis. CD48GN is characterized by glomerular hypertrophy with mesangial expansion, proliferation and leukocytic infiltration. Immune complexes deposit in mesangium and in sub-endothelial, sub-epithelial and intramembranous sites along the glomerular basement membrane. Afflicted mice have low-grade proteinuria, intermittent hematuria and their progressive renal injury manifests with elevated urine NGAL levels and with uremia. In contrast to the lupus-like B6.129CD48(-/-) animals, neither BALB.129CD48(-/-) mice nor B6 {\texttimes} BALB/c F1.129CD48(-/-) progeny have autoimmune traits, indicating that B6-specific background genes modulate the effect of CD48 on lupus nephritis in a recessive manner.},
	keywords = {Animals, Antigen-Antibody Complex, Antigens, CD, Autoimmunity, Disease Models, Animal, Female, Genes, Recessive, Glomerulonephritis, Kidney Glomerulus, Lupus Erythematosus, Systemic, Lupus Nephritis, Mice, Mice, 129 Strain, Mice, Inbred BALB C, Mice, Inbred MRL lpr, Mice, Knockout},
	issn = {1095-9157},
	doi = {10.1016/j.jaut.2011.03.004},
	author = {Koh, Anna E and Njoroge, Sarah W and Feliu, Marianela and Cook, Alexis and Selig, Martin K and Latchman, Yvette E and Sharpe, Arlene H and Colvin, Robert B and Paul, Elahna}
}
@article {542191,
	title = {Antigen-specific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection.},
	journal = {Proc Natl Acad Sci U S A},
	volume = {108},
	number = {52},
	year = {2011},
	month = {2011 Dec 27},
	pages = {21182-7},
	abstract = {CD4 T cells play a critical role in regulating CD8 T-cell responses during chronic viral infection. Several studies in animal models and humans have shown that the absence of CD4 T-cell help results in severe dysfunction of virus-specific CD8 T cells. However, whether function can be restored in already exhausted CD8 T cells by providing CD4 T-cell help at a later time remains unexplored. In this study, we used a mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection to address this question. Adoptive transfer of LCMV-specific CD4 T cells into chronically infected mice restored proliferation and cytokine production by exhausted virus-specific CD8 T cells and reduced viral burden. Although the transferred CD4 T cells were able to enhance function in exhausted CD8 T cells, these CD4 T cells expressed high levels of the programmed cell death (PD)-1 inhibitory receptor. Blockade of the PD-1 pathway increased the ability of transferred LCMV-specific CD4 T cells to produce effector cytokines, improved rescue of exhausted CD8 T cells, and resulted in a striking reduction in viral load. These results suggest that CD4 T-cell immunotherapy alone or in conjunction with blockade of inhibitory receptors may be a promising approach for treating CD8 T-cell dysfunction in chronic infections and cancer.},
	keywords = {Adoptive Transfer, Animals, Arenaviridae Infections, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cytokines, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Immunotherapy, Lymphocytic choriomeningitis virus, Mice, Mice, Inbred C57BL, Mice, Transgenic, Programmed Cell Death 1 Receptor, Statistics, Nonparametric},
	issn = {1091-6490},
	doi = {10.1073/pnas.1118450109},
	author = {Aubert, Rachael D and Kamphorst, Alice O and Sarkar, Surojit and Vezys, Vaiva and Ha, Sang-Jun and Barber, Daniel L and Ye, Lilin and Sharpe, Arlene H and Freeman, Gordon J and Ahmed, Rafi}
}
@article {542201,
	title = {The pathogenic Th17 cell response to major schistosome egg antigen is sequentially dependent on IL-23 and IL-1β.},
	journal = {J Immunol},
	volume = {187},
	number = {10},
	year = {2011},
	month = {2011 Nov 15},
	pages = {5328-35},
	abstract = {CBA/J mice infected with the helminth Schistosoma mansoni develop severe CD4 T cell-mediated hepatic granulomatous inflammation against parasite eggs associated with a robust Th17 cell response. We investigated the requisites for Th17 cell development using novel CD4 T cells expressing a transgenic TCR specific for the major Sm-p40 egg Ag, which produce IL-17 when stimulated with live schistosome eggs. Neutralization of IL-23 or blockade of the IL-1 receptor, but not IL-6 neutralization, abrogated egg-induced IL-17 secretion by transgenic T cells, whereas exogenous IL-23 or IL-1β reconstituted their ability to produce IL-17 when stimulated by syngeneic IL-12p40-deficient dendritic cells. Kinetic analysis demonstrated that IL-17 production was initiated by IL-23 and amplified by IL-1β. Significantly, schistosome-infected IL-12p40-deficient or IL-1R antagonist-treated CBA/J mice developed markedly reduced hepatic immunopathology with a dampened egg Ag-specific IL-17 response. These results demonstrate that the IL-23-IL-1-IL-17 axis has a central role in the development of severe schistosome egg-induced immunopathology.},
	keywords = {Animals, Antigens, Helminth, Epitopes, T-Lymphocyte, Helminth Proteins, Interferon-gamma, Interleukin-17, Interleukin-1beta, Interleukin-23, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Transgenic, Schistosoma mansoni, Schistosomiasis mansoni, Th17 Cells},
	issn = {1550-6606},
	doi = {10.4049/jimmunol.1101445},
	author = {Shainheit, Mara G and Lasocki, Krzysztof W and Finger, Eduardo and Larkin, Bridget M and Smith, Patrick M and Sharpe, Arlene H and Dinarello, Charles A and Rutitzky, Laura I and Stadecker, Miguel J}
}
@article {542206,
	title = {Physiologic control of IDO competence in splenic dendritic cells.},
	journal = {J Immunol},
	volume = {187},
	number = {5},
	year = {2011},
	month = {2011 Sep 1},
	pages = {2329-35},
	abstract = {Dendritic cells (DCs) competent to express the regulatory enzyme IDO in mice are a small but distinctive subset of DCs. Previously, we reported that a high-dose systemic CpG treatment to ligate TLR9 in vivo induced functional IDO exclusively in splenic CD19(+) DCs, which stimulated resting Foxp3-lineage regulatory T cells (Tregs) to rapidly acquire potent suppressor activity. In this paper, we show that IDO was induced in spleen and peripheral lymph nodes after CpG treatment in a dose-dependent manner. Induced IDO suppressed local T cell responses to exogenous Ags and inhibited proinflammatory cytokine expression in response to TLR9 ligation. IDO induction did not occur in T cell-deficient mice or in mice with defective B7 or programmed death (PD)-1 costimulatory pathways. Consistent with these findings, CTLA4 or PD-1/PD-ligand costimulatory blockade abrogated IDO induction and prevented Treg activation via IDO following high-dose CpG treatment. Consequently, CD4(+)CD25(+) T cells uniformly expressed IL-17 shortly after TLR9 ligation. These data support the hypothesis that constitutive interactions from activated T cells or Tregs and IDO-competent DCs via concomitant CTLA4{\textrightarrow}B7 and PD-1{\textrightarrow}PD-ligand signals maintain the default potential to regulate T cell responsiveness via IDO. Acute disruption of these nonredundant interactions abrogated regulation via IDO, providing novel perspectives on the proinflammatory effects of costimulatory blockade therapies. Moreover, interactions between IDO-competent DCs and activated T cells in lymphoid tissues may attenuate proinflammatory responses to adjuvants such as TLR ligands.},
	keywords = {Animals, Antigen Presentation, Cell Separation, Dendritic Cells, Flow Cytometry, Immunohistochemistry, Indoleamine-Pyrrole 2,3,-Dioxygenase, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Transgenic, Oligodeoxyribonucleotides, Spleen, T-Lymphocytes, Regulatory, Toll-Like Receptor 9},
	issn = {1550-6606},
	doi = {10.4049/jimmunol.1100276},
	author = {Baban, Babak and Chandler, Phillip R and Johnson, Burles A and Huang, Lei and Li, Minghui and Sharpe, Marlon L and Francisco, Loise M and Sharpe, Arlene H and Blazar, Bruce R and Munn, David H and Mellor, Andrew L}
}
@article {1051236,
	title = {Diode-pumped mode-locked Yb:LuScO(3) single crystal laser with 74 fs pulse duration},
	journal = {Opt Lett},
	volume = {35},
	number = {4},
	year = {2010},
	month = {2010 Feb 15},
	pages = {511-3},
	abstract = {The mode locking of the mixed sesquioxide single crystal Yb:LuScO(3) is demonstrated. This crystal is locally disordered and has the broadest emission spectrum of all sesquioxides known so far. Pulse durations as short as 111 and 74 fs were obtained using the semiconductor saturable absorber mirror and Kerr-lens mode locking, respectively. The latter regime was reached using a two-section distributed Bragg-reflector tapered diode laser as a pump source.},
	issn = {1539-4794},
	doi = {10.1364/OL.35.000511},
	author = {Schmidt, Andreas and Petrov, Valentin and Griebner, Uwe and Peters, Rigo and Petermann, Klaus and Huber, G{\"u}nter and Fiebig, Christian and Paschke, Katrin and Erbert, G{\"o}tz}
}
@article {542321,
	title = {PD-L1 and PD-L2 modulate airway inflammation and iNKT-cell-dependent airway hyperreactivity in opposing directions.},
	journal = {Mucosal Immunol},
	volume = {3},
	number = {1},
	year = {2010},
	month = {2010 Jan},
	pages = {81-91},
	abstract = {Interactions of the inhibitory receptor programmed death-1 (PD-1) with its ligands, programmed death ligand (PD-L)1 and PD-L2, regulate T-cell activation and tolerance. In this study, we investigated the role of PD-L1 and PD-L2 in regulating invariant natural killer T (iNKT)-cell-mediated airway hyperreactivity (AHR) in a murine model of asthma. We found that the severity of AHR and airway inflammation is significantly greater in PD-L2(-/-) mice compared with wild-type mice after either ovalbumin (OVA) sensitization and challenge or administration of alpha-galactosylceramide (alpha-GalCer). iNKT cells from PD-L2(-/-) mice produced significantly more interleukin (IL)-4 than iNKT cells from control mice. Moreover, blockade of PD-L2 interactions of wild-type iNKT cells in vitro with monoclonal antibodies (mAbs) resulted in significantly enhanced levels of IL-4 production. In contrast, PD-L1(-/-) mice showed significantly reduced AHR and enhanced production of interferon-gamma (IFN-gamma) by iNKT cells. iNKT-deficient Jalpha18(-/-) mice reconstituted with iNKT cells from PD-L2(-/-) mice developed high levels of AHR, whereas mice reconstituted with iNKT cells from PD-L1(-/-) mice developed lower levels of AHR compared with control. As PD-L2 is not expressed on iNKT cells but rather is expressed on lung dendritic cells (DCs), in which its expression is upregulated by allergen challenge or IL-4, these findings suggest an important role of PD-L2 on lung DCs in modulating asthma pathogenesis. These studies also indicate that PD-L1 and PD-L2 have important but opposing roles in the regulation of AHR and iNKT-cell-mediated activation.},
	keywords = {Animals, Antibodies, Blocking, Antigens, CD274, Antigens, CD80, Asthma, Cells, Cultured, Dendritic Cells, Female, Galactosylceramides, Interferon-gamma, Interleukin-4, Lung, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Knockout, Natural Killer T-Cells, Ovalbumin, Peptides, Programmed Cell Death 1 Ligand 2 Protein},
	issn = {1935-3456},
	doi = {10.1038/mi.2009.112},
	author = {Akbari, O and Stock, P and Singh, A K and Lombardi, V and Lee, W-L and Freeman, G. J. and Sharpe, A. H. and Umetsu, D T and Dekruyff, R H}
}
@article {542271,
	title = {The PD-1 pathway in tolerance and autoimmunity.},
	journal = {Immunol Rev},
	volume = {236},
	year = {2010},
	month = {2010 Jul},
	pages = {219-42},
	abstract = {Regulatory T cells (Tregs) and the PD-1: PD-ligand (PD-L) pathway are both critical to terminating immune responses. Elimination of either can result in the breakdown of tolerance and the development of autoimmunity. The PD-1: PD-L pathway can thwart self-reactive T cells and protect against autoimmunity in many ways. In this review, we highlight how PD-1 and its ligands defend against potentially pathogenic self-reactive effector T cells by simultaneously harnessing two mechanisms of peripheral tolerance: (i) the promotion of Treg development and function and (ii) the direct inhibition of potentially pathogenic self-reactive T cells that have escaped into the periphery. Treg cells induced by the PD-1 pathway may also assist in maintaining immune homeostasis, keeping the threshold for T-cell activation high enough to safeguard against autoimmunity. PD-L1 expression on non-hematopoietic cells as well as hematopoietic cells endows PD-L1 with the capacity to promote Treg development and enhance Treg function in lymphoid organs and tissues that are targets of autoimmune attack. At sites where transforming growth factor-beta is present (e.g. sites of immune privilege or inflammation), PD-L1 may promote the de novo generation of Tregs. When considering the consequences of uncontrolled immunity, it would be therapeutically advantageous to manipulate Treg development and sustain Treg function. Thus, this review also discusses how the PD-1 pathway regulates a number of autoimmune diseases and the therapeutic potential of PD-1: PD-L modulation.},
	keywords = {Animals, Antigens, CD, Antigens, CD274, Apoptosis Regulatory Proteins, Autoimmune Diseases, Autoimmunity, Humans, Immune Tolerance, Models, Immunological, Programmed Cell Death 1 Receptor, Signal Transduction, T-Lymphocytes, Regulatory},
	issn = {1600-065X},
	doi = {10.1111/j.1600-065X.2010.00923.x},
	author = {Francisco, Loise M and Sage, Peter T and Sharpe, Arlene H}
}
@article {542286,
	title = {PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells.},
	journal = {Nat Immunol},
	volume = {11},
	number = {6},
	year = {2010},
	month = {2010 Jun},
	pages = {535-42},
	abstract = {Memory B and plasma cells (PCs) are generated in the germinal center (GC). Because follicular helper T cells (T(FH) cells) have high expression of the immunoinhibitory receptor PD-1, we investigated the role of PD-1 signaling in the humoral response. We found that the PD-1 ligands PD-L1 and PD-L2 were upregulated on GC B cells. Mice deficient in PD-L2 (Pdcd1lg2(-/-)), PD-L1 and PD-L2 (Cd274(-/-)Pdcd1lg2(-/-)) or PD-1 (Pdcd1(-/-)) had fewer long-lived PCs. The mechanism involved more GC cell death and less T(FH) cell cytokine production in the absence of PD-1; the effect was selective, as remaining PCs had greater affinity for antigen. PD-1 expression on T cells and PD-L2 expression on B cells controlled T(FH) cell and PC numbers. Thus, PD-1 regulates selection and survival in the GC, affecting the quantity and quality of long-lived PCs.},
	keywords = {Animals, Antigens, Surface, Apoptosis Regulatory Proteins, B-Lymphocytes, Cell Differentiation, Cell Survival, Germinal Center, Mice, Mice, Knockout, Plasma Cells, Programmed Cell Death 1 Receptor},
	issn = {1529-2916},
	doi = {10.1038/ni.1877},
	author = {Good-Jacobson, Kim L and Szumilas, Courtney G and Chen, Lieping and Sharpe, Arlene H and Tomayko, Mary M and Shlomchik, Mark J}
}
@article {542281,
	title = {PD-L1 has distinct functions in hematopoietic and nonhematopoietic cells in regulating T cell responses during chronic infection in mice.},
	journal = {J Clin Invest},
	volume = {120},
	number = {7},
	year = {2010},
	month = {2010 Jul},
	pages = {2508-15},
	abstract = {The inhibitory receptor programmed death 1 (PD-1) is upregulated on antigen-specific CD8+ T cells during persistent viral infections. Interaction with PD-1 ligand 1 (PD-L1) contributes to functional exhaustion of responding T cells and may limit immunopathology during infection. PD-L1 is expressed on both hematopoietic and nonhematopoietic cells in tissues. However, the exact roles of PD-L1 on hematopoietic versus nonhematopoietic cells in modulating immune responses are unclear. Here we used bone marrow chimeric mice to examine the effects of PD-L1 deficiency in hematopoietic or nonhematopoietic cells during lymphocytic choriomeningitis virus clone 13 (LCMV CL-13) infection. We found that PD-L1 expression on hematopoietic cells inhibited CD8+ T cell numbers and function after LCMV CL-13 infection. In contrast, PD-L1 expression on nonhematopoietic cells limited viral clearance and immunopathology in infected tissues. Together, these data demonstrate that there are distinct roles for PD-L1 on hematopoietic and nonhematopoietic cells in regulating CD8+ T cell responses and viral clearance during chronic viral infection.},
	keywords = {Animals, Bone Marrow, Chronic Disease, Female, Ligands, Lymphocyte Count, Lymphocytic Choriomeningitis, Mice, Mice, Inbred C57BL, Mice, Knockout, T-Lymphocytes, Virus Diseases},
	issn = {1558-8238},
	doi = {10.1172/JCI40040},
	author = {Mueller, Scott N and Vanguri, Vijay K and Ha, Sang-Jun and West, Erin E and Keir, Mary E and Glickman, Jonathan N and Sharpe, Arlene H and Ahmed, Rafi}
}
@article {542276,
	title = {Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia.},
	journal = {Blood},
	volume = {116},
	number = {14},
	year = {2010},
	month = {2010 Oct 7},
	pages = {2484-93},
	abstract = {Tumor-induced immune defects can weaken host immune response and permit tumor cell growth. In a systemic model of murine acute myeloid leukemia (AML), tumor progression resulted in increased regulatory T cells (Treg) and elevation of program death-1 (PD-1) expression on CD8(+) cytotoxic T cells (CTLs) at the tumor site. PD-1 knockout mice were more resistant to AML despite the presence of similar percentage of Tregs compared with wild type. In vitro, intact Treg suppression of CD8(+) T-cell responses was dependent on PD-1 expression by T cells and Tregs and PD-L1 expression by antigen-presenting cells. In vivo, the function of adoptively transferred AML-reactive CTLs was reduced by AML-associated Tregs. Anti-PD-L1 monoclonal antibody treatment increased the proliferation and function of CTLs at tumor sites, reduced AML tumor burden, and resulted in long-term survivors. Treg depletion followed by PD-1/PD-L1 blockade showed superior efficacy for eradication of established AML. These data demonstrated that interaction between PD-1 and PD-L1 can facilitate Treg-induced suppression of T-effector cells and dampen the antitumor immune response. PD-1/PD-L1 blockade coupled with Treg depletion represents an important new approach that can be readily translated into the clinic to improve the therapeutic efficacy of adoptive AML-reactive CTLs in advanced AML disease.},
	keywords = {Animals, Antibodies, Monoclonal, Antigens, CD274, Antigens, CD8, Antigens, CD80, Antigens, Surface, Apoptosis Regulatory Proteins, Gene Expression Regulation, Leukemic, Leukemia, Myeloid, Acute, Lymphocyte Depletion, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Peptides, Programmed Cell Death 1 Receptor, T-Lymphocytes, Cytotoxic, T-Lymphocytes, Regulatory},
	issn = {1528-0020},
	doi = {10.1182/blood-2010-03-275446},
	author = {Zhou, Qing and Munger, Meghan E and Highfill, Steven L and Tolar, Jakub and Weigel, Brenda J and Riddle, Megan and Sharpe, Arlene H and Vallera, Daniel A and Azuma, Miyuki and Levine, Bruce L and June, Carl H and Murphy, William J and Munn, David H and Blazar, Bruce R}
}
@article {542301,
	title = {Regulation of T-cell chemotaxis by programmed death-ligand 1 (PD-L1) in dry eye-associated corneal inflammation.},
	journal = {Invest Ophthalmol Vis Sci},
	volume = {51},
	number = {7},
	year = {2010},
	month = {2010 Jul},
	pages = {3418-23},
	abstract = {PURPOSE. Given that dry eye disease (DED) is associated with T cell-mediated inflammation of the ocular surface and that PD-L1 is an important negative or inhibitory regulator of immune responses constitutively expressed at high levels by corneal epithelial cells, the authors studied the expression and function of PD-L1 in DED. METHODS. Dry eye was induced in untreated wild-type mice, PD-L1(-/-) mice, and wild-type mice treated with anti-PD-L1 antibody by exposing these mice to a desiccating environment in the controlled environment chamber modified with subcutaneous administration of scopolamine. Real-time PCR was used to quantify the expression of chemokine gene transcript levels of multiple CC and CXC chemokine ligands and receptors. Epifluorescence microscopy was used to evaluate corneal infiltration of CD3(+) T cells after immunohistochemical staining. RESULTS. The increased expression of specific chemokine ligands and receptors in PD-L1(-/-) corneas of normal mice is associated with significant increases in T-cell homing into these corneas. Similar, and more enhanced, increases in T-cell infiltration were observed in PD-L1(-/-) DED mice or DED mice treated with anti-PD-L1 antibody compared with controls. In addition, the authors found significantly decreased expression of PD-L1 by corneal epithelial cells in DED and significantly increased corneal fluorescein staining score with PD-L1 functional blockade using anti-PD-L1 antibody. CONCLUSIONS. Downregulation of corneal epithelial PD-L1 amplifies dry eye-associated corneal inflammation and epitheliopathy by increasing the expression of chemokine ligands and receptors that promote T-cell homing to the ocular surface.},
	keywords = {Animals, Antibodies, Blocking, Antigens, CD274, Antigens, CD3, Antigens, CD80, Cell Movement, Chemokines, Chemotaxis, Leukocyte, Disease Models, Animal, Dry Eye Syndromes, Epithelium, Corneal, Female, Fluorophotometry, Gene Expression, Immunohistochemistry, Keratitis, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Peptides, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes},
	issn = {1552-5783},
	doi = {10.1167/iovs.09-3684},
	author = {El Annan, Jaafar and Goyal, Sunali and Zhang, Qiang and Freeman, Gordon J and Sharpe, Arlene H and Dana, Reza}
}
@article {542291,
	title = {Role of PD-1 in regulating acute infections.},
	journal = {Curr Opin Immunol},
	volume = {22},
	number = {3},
	year = {2010},
	month = {2010 Jun},
	pages = {397-401},
	abstract = {While the role of PD-1 in inhibiting immunity during chronic infections is well established, its functions during acute infections are much less clear. The PD-1 pathway can dampen CD8 T cell responses during some acute infections and restrain responses by {\textquoteright}helpless{\textquoteright} CD8 memory T cells. An emerging role for PD-1 in innate immunity has been revealed by recent studies showing that PD-1 can limit function of DC and macrophages as well as T cell independent B cell responses. Thus, PD-1 can influence adaptive immune responses during acute infections, though precisely how this regulation occurs is only just beginning to be appreciated.},
	keywords = {Acute Disease, Animals, Antigens, Differentiation, Cell Differentiation, Gene Expression Regulation, Humans, Immunologic Memory, Infection, Lymphocyte Activation, Mice, Programmed Cell Death 1 Receptor, T-Lymphocytes},
	issn = {1879-0372},
	doi = {10.1016/j.coi.2010.03.007},
	author = {Brown, Keturah E and Freeman, Gordon J and Wherry, E John and Sharpe, Arlene H}
}
@article {542296,
	title = {Taming tissue-specific T cells: CTLA-4 reins in self-reactive T cells.},
	journal = {Nat Immunol},
	volume = {11},
	number = {2},
	year = {2010},
	month = {2010 Feb},
	pages = {109-11},
	keywords = {Animals, Antigens, CD, CTLA-4 Antigen, Mice, Self Tolerance, T-Lymphocytes},
	issn = {1529-2916},
	doi = {10.1038/ni0210-109},
	author = {Paterson, Alison M and Sharpe, Arlene H}
}
@article {542366,
	title = {The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells.},
	journal = {Nat Immunol},
	volume = {10},
	number = {2},
	year = {2009},
	month = {2009 Feb},
	pages = {167-75},
	abstract = {The inducible costimulatory molecule ICOS has been suggested to be important in the development of interleukin 17 (IL-17)-producing helper T cells (T(H)-17 cells) and of follicular helper T cells (T(FH) cells). Here we show that ICOS-deficient mice had no defect in T(H)-17 differentiation but had fewer T(H)-17 cells after IL-23 stimulation and fewer T(FH) cells. We also show that T(FH) cells produced IL-17 and that T(FH) cells in ICOS-deficient mice were defective in IL-17 production. Both T(H)-17 and T(FH) cells had higher expression of the transcription factor c-Maf. Genetic loss of c-Maf resulted in a defect in IL-21 production and fewer T(H)-17 and T(FH) cells. Thus our data suggest that ICOS-induced c-Maf regulates IL-21 production that in turn regulates the expansion of T(H)-17 and T(FH) cells.},
	keywords = {Animals, Antigens, Differentiation, T-Lymphocyte, Cell Differentiation, Cell Proliferation, Encephalomyelitis, Autoimmune, Experimental, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Gene Expression Regulation, Inducible T-Cell Co-Stimulator Protein, Interleukin-17, Interleukins, Mice, Mice, Transgenic, Oligonucleotide Array Sequence Analysis, Proto-Oncogene Proteins c-maf, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocyte Subsets, T-Lymphocytes, Helper-Inducer},
	issn = {1529-2916},
	doi = {10.1038/ni.1690},
	author = {Bauquet, Aurelie T and Jin, Hulin and Paterson, Alison M and Mitsdoerffer, Meike and Ho, I-Cheng and Sharpe, Arlene H and Kuchroo, Vijay K}
}
@article {542361,
	title = {Ctla-4 controls regulatory T cell peripheral homeostasis and is required for suppression of pancreatic islet autoimmunity.},
	journal = {J Immunol},
	volume = {182},
	number = {1},
	year = {2009},
	month = {2009 Jan 1},
	pages = {274-82},
	abstract = {The CTLA-4 pathway is recognized as a major immune inhibitory axis and is a key therapeutic target for augmenting antitumor immunity or curbing autoimmunity. CTLA-4-deficient mice provide the archetypal example of dysregulated immune homeostasis, developing lethal lymphoproliferation with multiorgan inflammation. In this study, we show that surprisingly these mice have an enlarged population of Foxp3(+) regulatory T cells (Treg). The increase in Treg is associated with normal thymic output but enhanced proliferation of Foxp3(+) cells in the periphery. We confirmed the effect of CTLA-4 deficiency on the Treg population using OVA-specific Treg which develop normally in the absence of CTLA-4, but show increased proliferation in response to peripheral self-Ag. Functional analysis revealed that Ag-specific Treg lacking CTLA-4 were unable to regulate disease in an adoptive transfer model of diabetes. Collectively, these data suggest that the proliferation of Treg in the periphery is tuned by CTLA-4 signals and that Treg expression of CTLA-4 is required for regulation of pancreas autoimmunity.},
	keywords = {Animals, Antigens, CD, Autoimmune Diseases, Cell Differentiation, Cell Proliferation, CTLA-4 Antigen, Diabetes Mellitus, Type 1, Forkhead Transcription Factors, Homeostasis, Immunosuppressive Agents, Islets of Langerhans, Lymphoproliferative Disorders, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Transgenic, Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes, Regulatory},
	issn = {1550-6606},
	author = {Schmidt, Emily M and Wang, Chun Jing and Ryan, Gemma A and Clough, Louise E and Qureshi, Omar S and Goodall, Margaret and Abbas, Abul K and Sharpe, Arlene H and Sansom, David M and Walker, Lucy S K}
}
@article {542316,
	title = {B7-1/2, but not PD-L1/2 molecules, are required on IL-10-treated tolerogenic DC and DC-derived exosomes for in vivo function.},
	journal = {Eur J Immunol},
	volume = {39},
	number = {11},
	year = {2009},
	month = {2009 Nov},
	pages = {3084-90},
	abstract = {Costimulatory molecules, such as B7-1/2 and PD-L1/2 play an important role in the function of APC. The regulation of the surface levels of costimulatory molecules is one mechanism by which APC maintain the balance between tolerance and immunity. We examined the contributions of B7-1/2 and PD-L1/2 to the function of IL-10-treated, immunosuppressive DC as well as therapeutic exosomes derived from these DC. IL-10 treatment of DC significantly downregulated surface expression of MHC II, B7-1, B7-2, and decreased levels of MHC I and PD-L2. IL-10 treatment of DC resulted in a modified costimulatory profile of DC-secreted exosomes with a reduction in B7-1, PD-L1 and PD-L2. We further demonstrate that absence of B7-1 or B7-2 on donor DC results in a loss of ability of IL-10-treated DC and their exosomes to suppress the delayed-type hypersensitivity response, whereas IL-10-treated DC deficient in PD-L1/2 as well as their secreted exosomes retained the ability to suppress delayed-type hypersensitivity responses. We conclude that B7-1 and B7-2, but not PD-L1 and PD-L2, on IL-10-treated DC and DC-derived exosomes play a critical role in immunosuppressive functions of both DC and exosomes.},
	keywords = {Animals, Antigen Presentation, Antigen-Presenting Cells, Antigens, CD274, Antigens, CD80, Antigens, CD86, Blotting, Western, Cell Separation, Dendritic Cells, Enzyme-Linked Immunosorbent Assay, Exosomes, Female, Flow Cytometry, Histocompatibility Antigens Class I, Histocompatibility Antigens Class II, Hypersensitivity, Delayed, Immune Tolerance, Interleukin-10, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Peptides, Programmed Cell Death 1 Ligand 2 Protein},
	issn = {1521-4141},
	doi = {10.1002/eji.200939407},
	author = {Ruffner, Melanie A and Kim, Seon Hee and Bianco, Nicole R and Francisco, Loise M and Sharpe, Arlene H and Robbins, Paul D}
}
@article {542346,
	title = {Constitutive neuronal expression of the immune regulator, programmed death 1 (PD-1), identified during experimental autoimmune uveitis.},
	journal = {Ocul Immunol Inflamm},
	volume = {17},
	number = {1},
	year = {2009},
	month = {2009 Jan-Feb},
	pages = {47-55},
	abstract = {PURPOSE: Programmed death-1 (PD-1) ligation downregulates active lymphocyte responses. The authors tested whether PD-1 or its ligands are expressed in the posterior segment during active intraocular inflammation.

METHODS: Experimental autoimmune uveitis (EAU) was induced using interphotoreceptor retinoid-binding protein (IRBP 161-180). Ocular inflammation was evaluated by histology and expression of PD-1 ligand tested by immunohistochemistry. PD-1 expression was evaluated by immunohistochemistry, RT-PCR, and Western immunoblotting.

RESULTS: Using immunohistochemistry, PD-1, but not its ligands, was constitutively expressed in retinal neurons of naive mouse retina. Both PD-1 and its ligands were observed, as expected, in sites of active inflammation.

CONCLUSIONS: PD-1 and its ligands were expressed in sites of active inflammation, in accordance with many other models of inflammatory disease. Surprisingly, PD-1, not previously described outside the immune system, was constitutively expressed in retinal neurons, raising the possibility that PD-1 signaling may be important for neuronal function in the absence of an inflammatory insult.},
	keywords = {Animals, Antigens, CD274, Antigens, CD80, Antigens, Surface, Apoptosis Regulatory Proteins, Autoimmune Diseases, Blotting, Western, Brain, Disease Models, Animal, Eye Proteins, Immunoenzyme Techniques, Male, Membrane Glycoproteins, Mice, Peptide Fragments, Peptides, Programmed Cell Death 1 Ligand 2 Protein, Programmed Cell Death 1 Receptor, Retinol-Binding Proteins, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Sequence Analysis, DNA, Uveitis, Posterior},
	issn = {1744-5078},
	doi = {10.1080/09273940802491884},
	author = {Chen, Ling and Pai, Vicky and Levinson, Ralph and Sharpe, Arlene H and Freeman, Gordon J and Braun, Jonathan and Gordon, Lynn K}
}
@article {542326,
	title = {Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells.},
	journal = {J Immunol},
	volume = {183},
	number = {2},
	year = {2009},
	month = {2009 Jul 15},
	pages = {797-801},
	abstract = {IL-27 has recently been identified as a differentiation factor for the generation of IL-10-producing regulatory type 1 (Tr1) T cells. However, how IL-27 induces the expansion of Tr1 cells has not been elucidated. In this study we demonstrate that IL-27 drives the expansion and differentiation of IL-10-producing murine Tr1 cells by inducing three key elements: the transcription factor c-Maf, the cytokine IL-21, and the costimulatory receptor ICOS. IL-27-driven c-Maf expression transactivates IL-21 production, which acts as an autocrine growth factor for the expansion and/or maintenance of IL-27-induced Tr1 cells. ICOS further promotes IL-27-driven Tr1 cells. Each of those elements is essential, because loss of c-Maf, IL-21-signaling, or ICOS decreases the frequency of IL-27-induced differentiation of IL-10-producing Tr1 cells.},
	keywords = {Animals, Antigens, Differentiation, T-Lymphocyte, Cell Differentiation, Inducible T-Cell Co-Stimulator Protein, Interleukin-10, Interleukins, Mice, Proto-Oncogene Proteins c-maf, T-Lymphocytes, Regulatory, Transcriptional Activation},
	issn = {1550-6606},
	doi = {10.4049/jimmunol.0901233},
	author = {Pot, Caroline and Jin, Hulin and Awasthi, Amit and Liu, Sue Min and Lai, Chen-Yen and Madan, Rajat and Sharpe, Arlene H and Karp, Christopher L and Miaw, Shi-Chuen and Ho, I-Cheng and Kuchroo, Vijay K}
}
@article {542351,
	title = {Enhanced selection of FoxP3+ T-regulatory cells protects CTLA-4-deficient mice from CNS autoimmune disease.},
	journal = {Proc Natl Acad Sci U S A},
	volume = {106},
	number = {9},
	year = {2009},
	month = {2009 Mar 3},
	pages = {3306-11},
	abstract = {It is generally acknowledged that cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4/CD152) plays a pivotal role in the regulation of T-cell activation and the establishment of self-tolerance in the periphery. CTLA-4-deficient (CTLA-4KO) mice develop a lymphoproliferative disorder and die within 4 weeks of birth, suggesting a role for CTLA-4 in T-cell homeostasis or the development and activity of T-regulatory (Treg) cells. To study the role of CTLA-4 in the control of experimental autoimmune encephalomyelitis (EAE), we have generated a CTLA-4KO mouse in which >90\% of all CD4(+) T cells bear a Vbeta8.2 transgenic T-cell receptor that is specific for myelin basic protein peptide Ac1-9 (ASQKRPSQR). These mice do not develop spontaneous lymphoproliferative disease or EAE and are resistant to disease induction. This correlates with a higher frequency of functional FoxP3(+) Treg cells in the spleen and thymus of CTLA-4KO mice. The absence of CTLA-4-mediated suppression of CD28 signaling resulted in the early expression of FoxP3 on double-positive cells in the thymic cortex. We conclude that CTLA-4 is not essential for the peripheral function of FoxP3(+) Treg cells but plays a pivotal role in their thymic selection.},
	keywords = {Animals, Antigens, CD, CTLA-4 Antigen, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Female, Forkhead Transcription Factors, Gene Deletion, Interleukin-2 Receptor alpha Subunit, Male, Mice, Mice, Knockout, Spleen, Thymus Gland},
	issn = {1091-6490},
	doi = {10.1073/pnas.0803186106},
	author = {Verhagen, Johan and Gabrysov{\'a}, Leona and Minaee, Sophie and Sabatos, Catherine A and Anderson, Graham and Sharpe, Arlene H and Wraith, David C}
}
@article {542311,
	title = {Genetic evidence that the differential expression of the ligand-independent isoform of CTLA-4 is the molecular basis of the Idd5.1 type 1 diabetes region in nonobese diabetic mice.},
	journal = {J Immunol},
	volume = {183},
	number = {8},
	year = {2009},
	month = {2009 Oct 15},
	pages = {5146-57},
	abstract = {Idd5.1 regulates T1D susceptibility in nonobese diabetic (NOD) mice and has two notable candidate genes, Ctla4 and Icos. Reduced expression of one of the four CTLA-4 isoforms, ligand-independent CTLA-4 (liCTLA-4), which inhibits in vitro T cell activation and cytokine production similarly to full-length CTLA-4 (flCTLA-4), has been hypothesized to increase type 1 diabetes (T1D) susceptibility. However, further support of this hypothesis is required since the Idd5.1 haplotypes of the diabetes-susceptible NOD and the resistant B10 strains differ throughout Ctla4 and Icos. Using haplotype analysis and the generation of novel Idd5.1-congenic strains that differ at the disease-associated Ctla4 exon 2 single-nucleotide polymorphism, we demonstrate that increased expression of liCTLA-4 correlates with reduced T1D susceptibility. To directly assess the ability of liCTLA-4 to modulate T1D, we generated liCTLA-4-transgenic NOD mice and compared their diabetes susceptibility to nontransgenic littermates. NOD liCTLA-4-transgenic mice were protected from T1D to the same extent as NOD.B10 Idd5.1-congenic mice, demonstrating that increased liCTLA-4 expression alone can account for disease protection. To further investigate the in vivo function of liCTLA-4, specifically whether liCTLA-4 can functionally replace flCTLA-4 in vivo, we expressed the liCTLA-4 transgene in CTLA-4(-/-) B6 mice. CTLA-4(-/-) mice expressing liCTLA-4 accumulated fewer activated effector/memory CD4(+) T cells than CTLA-4(-/-) mice and the transgenic mice were partially rescued from the multiorgan inflammation and early lethality caused by the disruption of Ctla4. These results suggest that liCTLA-4 can partially replace some functions of flCTLA-4 in vivo and that this isoform evolved to reinforce the function of flCTLA-4.},
	keywords = {Animals, Antigens, CD, Antigens, Differentiation, T-Lymphocyte, Autoimmunity, CTLA-4 Antigen, Diabetes Mellitus, Type 1, Genetic Predisposition to Disease, Haplotypes, Inducible T-Cell Co-Stimulator Protein, Interferon-gamma, Interleukin-17, Lymphocyte Activation, Mice, Mice, Inbred NOD, Mice, Knockout, Mice, Transgenic, Polymorphism, Single Nucleotide, Protein Isoforms, T-Lymphocytes},
	issn = {1550-6606},
	doi = {10.4049/jimmunol.0802610},
	author = {Araki, Manabu and Chung, Denise and Liu, Sue and Rainbow, Daniel B and Chamberlain, Giselle and Garner, Valerie and Hunter, Kara M D and Vijayakrishnan, Lalitha and Peterson, Laurence B and Oukka, Mohamed and Sharpe, Arlene H and Sobel, Raymond and Kuchroo, Vijay K and Wicker, Linda S}
}
@article {542356,
	title = {Intestinal tolerance is converted to autoimmune enteritis upon PD-1 ligand blockade.},
	journal = {J Immunol},
	volume = {182},
	number = {4},
	year = {2009},
	month = {2009 Feb 15},
	pages = {2102-12},
	abstract = {The B7 family member programmed death-1 ligand (PD-L1) has been shown to play an inhibitory role in the regulation of T cell responses in several organs. However, the role of PD-L1 in regulating tolerance to self-Ags of the small intestine has not been previously addressed. In this study, we investigated the role of PD-L1 in CD8(+) T cell tolerance to an intestinal epithelium-specific Ag using the iFABP-tOVA transgenic mouse model, in which OVA is expressed as a self-Ag throughout the small intestine. Using adoptive transfer of naive OVA-specific CD8(+) T cells, we show that loss of PD-1:PD-L1 signaling, by either Ab-mediated PD-L1 blockade or transfer of PD-1(-/-) T cells, leads to considerable expansion of OVA-specific CD8(+) T cells and their differentiation into effector cells capable of producing proinflammatory cytokines. A fatal CD8(+) T cell-mediated inflammatory response develops rapidly against the small bowel causing destruction of the epithelial barrier, severe blunting of intestinal villi, and recruitment and activation of myeloid cells. This response is highly specific because immune destruction selectively targets the small intestine but not other organs. Collectively, these results indicate that loss of the PD-1:PD-L1 inhibitory pathway breaks CD8(+) T cell tolerance to intestinal self-Ag, thus leading to severe enteric autoimmunity.},
	keywords = {Adoptive Transfer, Animals, Antigens, CD274, Antigens, CD80, Antigens, Surface, Apoptosis Regulatory Proteins, Autoantigens, Autoimmune Diseases, CD8-Positive T-Lymphocytes, Cell Differentiation, Enteritis, Flow Cytometry, Immune Tolerance, Immunity, Mucosal, Intestines, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Transgenic, Ovalbumin, Peptides, Programmed Cell Death 1 Receptor},
	issn = {1550-6606},
	doi = {10.4049/jimmunol.0802769},
	author = {Reynoso, Erika D and Elpek, Kutlu G and Francisco, Loise and Bronson, Roderick and Bellemare-Pelletier, Ang{\'e}lique and Sharpe, Arlene H and Freeman, Gordon J and Turley, Shannon J}
}
@article {542336,
	title = {Mechanisms of costimulation.},
	journal = {Immunol Rev},
	volume = {229},
	number = {1},
	year = {2009},
	month = {2009 May},
	pages = {5-11},
	keywords = {Animals, Antigens, CD, Antigens, CD28, Antigens, CD80, Antigens, Differentiation, T-Lymphocyte, CTLA-4 Antigen, Humans, Inducible T-Cell Co-Stimulator Protein, Intracellular Signaling Peptides and Proteins, Lymphocyte Activation, Receptors, Antigen, T-Cell, Receptors, Tumor Necrosis Factor, Signal Transduction, T-Lymphocytes, Tumor Necrosis Factor-alpha},
	issn = {1600-065X},
	doi = {10.1111/j.1600-065X.2009.00784.x},
	author = {Sharpe, Arlene H}
}
@article {542341,
	title = {Role of the immune modulator programmed cell death-1 during development and apoptosis of mouse retinal ganglion cells.},
	journal = {Invest Ophthalmol Vis Sci},
	volume = {50},
	number = {10},
	year = {2009},
	month = {2009 Oct},
	pages = {4941-8},
	abstract = {PURPOSE: Mammalian programmed cell death (PD)-1 is a membrane-associated receptor regulating the balance between T-cell activation, tolerance, and immunopathology; however, its role in neurons has not yet been defined. The hypothesis that PD-1 signaling actively promotes retinal ganglion cell (RGC) death within the developing mouse retina was investigated.

METHODS: Mature retinal cell types expressing PD-1 were identified by immunofluorescence staining of vertical retina sections; developmental expression was localized by immunostaining and quantified by Western blot analysis. PD-1 involvement in developmental RGC survival was assessed in vitro using retinal explants and in vivo using PD-1 knockout mice. PD-1 ligand gene expression was detected by RT-PCR.

RESULTS: PD-1 is expressed in most adult RGCs and undergoes dynamic upregulation during the early postnatal window of retinal cell maturation and physiological programmed cell death (PCD). In vitro blockade of PD-1 signaling during this time selectively increases the survival of RGCs. Furthermore, PD-1-deficient mice show a selective increase in RGC number in the neonatal retina at the peak of developmental RGC death. Lastly, gene expression of the immune PD-1 ligand genes Pdcd1lg1 and Pdcd1lg2 was found throughout postnatal retina maturation.

CONCLUSIONS: These findings collectively support a novel role for a PD-1-mediated signaling pathway in developmental PCD during postnatal RGC maturation.},
	keywords = {Animals, Animals, Newborn, Antigens, CD274, Antigens, CD80, Antigens, Surface, Apoptosis, Apoptosis Regulatory Proteins, Blotting, Western, Cell Count, Cell Survival, Fluorescent Antibody Technique, Indirect, Gene Expression Regulation, Developmental, Ligands, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Peptides, Programmed Cell Death 1 Ligand 2 Protein, Programmed Cell Death 1 Receptor, Retina, Retinal Ganglion Cells, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Signal Transduction},
	issn = {1552-5783},
	doi = {10.1167/iovs.09-3602},
	author = {Chen, Ling and Sham, Caroline W and Chan, Ann M and Francisco, Loise M and Wu, Yin and Mareninov, Sergey and Sharpe, Arlene H and Freeman, Gordon J and Yang, Xian-Jie and Braun, Jonathan and Gordon, Lynn K}
}
@article {542331,
	title = {SnapShot: B7/CD28 costimulation.},
	journal = {Cell},
	volume = {137},
	number = {5},
	year = {2009},
	month = {2009 May 29},
	pages = {974-4.e1},
	keywords = {Animals, Antigen-Presenting Cells, Antigens, CD28, Antigens, CD80, Humans, T-Lymphocytes},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2009.05.015},
	author = {Paterson, Alison M and Vanguri, Vijay K and Sharpe, Arlene H}
}
@article {542306,
	title = {PD-L1 regulates the development, maintenance, and function of induced regulatory T cells.},
	journal = {J Exp Med},
	volume = {206},
	number = {13},
	year = {2009},
	month = {2009 Dec 21},
	pages = {3015-29},
	abstract = {Both the programmed death (PD) 1-PD-ligand (PD-L) pathway and regulatory T (T reg) cells are instrumental to the maintenance of peripheral tolerance. We demonstrate that PD-L1 has a pivotal role in regulating induced T reg (iT reg) cell development and sustaining iT reg cell function. PD-L1(-/-) antigen-presenting cells minimally convert naive CD4 T cells to iT reg cells, showing the essential role of PD-L1 for iT reg cell induction. PD-L1-coated beads induce iT reg cells in vitro, indicating that PD-L1 itself regulates iT reg cell development. Furthermore, PD-L1 enhances and sustains Foxp3 expression and the suppressive function of iT reg cells. The obligatory role for PD-L1 in controlling iT reg cell development and function in vivo is illustrated by a marked reduction in iT reg cell conversion and rapid onset of a fatal inflammatory phenotype in PD-L1(-/-)PD-L2(-/-) Rag(-/-) recipients of naive CD4 T cells. PD-L1 iT reg cell development is mediated through the down-regulation of phospho-Akt, mTOR, S6, and ERK2 and concomitant with the up-regulation of PTEN, all key signaling molecules which are critical for iT reg cell development. Thus, PD-L1 can inhibit T cell responses by promoting both the induction and maintenance of iT reg cells. These studies define a novel mechanism for iT reg cell development and function, as well as a new strategy for controlling T reg cell plasticity.},
	keywords = {Animals, Antigens, CD274, Antigens, CD45, Antigens, CD80, Carrier Proteins, Forkhead Transcription Factors, Lung, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Peptides, Phosphotransferases (Alcohol Group Acceptor), Programmed Cell Death 1 Ligand 2 Protein, Proto-Oncogene Proteins c-akt, Signal Transduction, T-Lymphocytes, Regulatory, TOR Serine-Threonine Kinases, Transforming Growth Factor beta},
	issn = {1540-9538},
	doi = {10.1084/jem.20090847},
	author = {Francisco, Loise M and Salinas, Victor H and Brown, Keturah E and Vanguri, Vijay K and Freeman, Gordon J and Kuchroo, Vijay K and Sharpe, Arlene H}
}
@article {542411,
	title = {PD-1 and its ligands in tolerance and immunity.},
	journal = {Annu Rev Immunol},
	volume = {26},
	year = {2008},
	month = {2008},
	pages = {677-704},
	abstract = {Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, deliver inhibitory signals that regulate the balance between T cell activation, tolerance, and immunopathology. Immune responses to foreign and self-antigens require specific and balanced responses to clear pathogens and tumors and yet maintain tolerance. Induction and maintenance of T cell tolerance requires PD-1, and its ligand PD-L1 on nonhematopoietic cells can limit effector T cell responses and protect tissues from immune-mediated tissue damage. The PD-1:PD-L pathway also has been usurped by microorganisms and tumors to attenuate antimicrobial or tumor immunity and facilitate chronic infection and tumor survival. The identification of B7-1 as an additional binding partner for PD-L1, together with the discovery of an inhibitory bidirectional interaction between PD-L1 and B7-1, reveals new ways the B7:CD28 family regulates T cell activation and tolerance. In this review, we discuss current understanding of the immunoregulatory functions of PD-1 and its ligands and their therapeutic potential.},
	keywords = {Animals, Antigens, CD, Antigens, CD274, Antigens, CD80, Apoptosis Regulatory Proteins, Humans, Immunity, Ligands, Models, Immunological, Programmed Cell Death 1 Receptor, Self Tolerance},
	issn = {0732-0582},
	doi = {10.1146/annurev.immunol.26.021607.090331},
	author = {Keir, Mary E and Butte, Manish J and Freeman, Gordon J and Sharpe, Arlene H}
}
@article {542406,
	title = {Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection.},
	journal = {J Exp Med},
	volume = {205},
	number = {3},
	year = {2008},
	month = {2008 Mar 17},
	pages = {543-55},
	abstract = {Therapeutic vaccination is a potentially promising strategy to enhance T cell immunity and viral control in chronically infected individuals. However, therapeutic vaccination approaches have fallen short of expectations, and effective boosting of antiviral T cell responses has not always been observed. One of the principal reasons for the limited success of therapeutic vaccination is that virus-specific T cells become functionally exhausted during chronic infections. We now provide a novel strategy for enhancing the efficacy of therapeutic vaccines. In this study, we show that blocking programmed death (PD)-1/PD-L1 inhibitory signals on exhausted CD8(+) T cells, in combination with therapeutic vaccination, synergistically enhances functional CD8(+) T cell responses and improves viral control in mice chronically infected with lymphocytic choriomeningitis virus. This combinatorial therapeutic vaccination was effective even in the absence of CD4(+) T cell help. Thus, our study defines a potent new approach to augment the efficacy of therapeutic vaccination by blocking negative signals. Such an approach may have broad applications in developing treatment strategies for chronic infections in general, and perhaps also for tumors.},
	keywords = {Animals, Antigen Presentation, Antigens, Surface, Apoptosis Regulatory Proteins, Arenaviridae Infections, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Chronic Disease, Dendritic Cells, Female, Lymphocytic choriomeningitis virus, Mice, Mice, Inbred C57BL, Programmed Cell Death 1 Receptor, Signal Transduction, Vaccines, Synthetic, Viral Vaccines},
	issn = {1540-9538},
	doi = {10.1084/jem.20071949},
	author = {Ha, Sang-Jun and Mueller, Scott N and Wherry, E John and Barber, Daniel L and Aubert, Rachael D and Sharpe, Arlene H and Freeman, Gordon J and Ahmed, Rafi}
}
@article {542401,
	title = {ICOS/ICOSL interaction is required for CD4+ invariant NKT cell function and homeostatic survival.},
	journal = {J Immunol},
	volume = {180},
	number = {8},
	year = {2008},
	month = {2008 Apr 15},
	pages = {5448-56},
	abstract = {The development of airway hyperreactivity (AHR), a cardinal feature of asthma, requires the presence of invariant NKT (iNKT) cells. In a mouse model of asthma, we demonstrated that the induction of AHR required ICOS costimulation of iNKT cells. ICOS was highly expressed on both naive and activated iNKT cells, and expression of ICOS was greater on the CD4(+) iNKT than on CD4(-) iNKT cells. Furthermore, the number of CD4(+) iNKT cells was significantly lower in spleens and livers of ICOS(-/-) and ICOSL(-/-) mice, and the remaining iNKT cells in ICOS(-/-) mice were dysfunctional and failed to reconstitute AHR when adoptively transferred into iNKT cell-deficient Jalpha18(-/-) mice. In addition, direct activation of iNKT cells with alpha-GalCer, which induced AHR in wild-type mice, failed to induce AHR in ICOS(-/-) mice. The failure of ICOS(-/-) iNKT cells to induce AHR was due in part to an inability of the ICOS(-/-) iNKT cells to produce IL-4 and IL-13 on activation. Moreover, survival of wild-type iNKT cells transferred into ICOSL(-/-) mice was greatly reduced due to the induction of apoptosis. These results indicate that ICOS costimulation plays a major role in induction of AHR by iNKT cells and is required for CD4(+) iNKT cell function, homeostasis, and survival in the periphery.},
	keywords = {Adoptive Transfer, Animals, Antigens, Differentiation, T-Lymphocyte, Apoptosis, Asthma, Bronchial Hyperreactivity, Bronchoalveolar Lavage Fluid, CD4-Positive T-Lymphocytes, Cytokines, Disease Models, Animal, Female, Inducible T-Cell Co-Stimulator Ligand, Inducible T-Cell Co-Stimulator Protein, Ligands, Mice, Mice, Inbred BALB C, Mice, Mutant Strains, Proteins, T-Lymphocyte Subsets},
	issn = {0022-1767},
	author = {Akbari, Omid and Stock, Philippe and Meyer, Everett H and Freeman, Gordon J and Sharpe, Arlene H and Umetsu, Dale T and DeKruyff, Rosemarie H}
}
@article {542371,
	title = {IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection.},
	journal = {Proc Natl Acad Sci U S A},
	volume = {105},
	number = {51},
	year = {2008},
	month = {2008 Dec 23},
	pages = {20428-33},
	abstract = {Suppression of T-cell responses by host-derived regulatory factors is a key event leading to viral persistence. Antibody blockade of either IL-10 or programmed death-ligand 1 (PD-L1) during viral persistence enhances T-cell function and reduces viral titers. Because blockade of these immunoregulatory networks represents a powerful approach to establish immune control during persistent infection, it is important to determine whether these immunoinhibitory factors act independently or jointly and if combined blockade of these factors further enhances T-cell immunity and viral clearance. Herein, we demonstrate that the IL-10 and PD-L1 immunosuppressive pathways are mechanistically distinct. As a result, simultaneous blockade of IL-10 and PD-L1 was significantly more effective in restoring antiviral T-cell responses than blockade of either alone, and led to substantially enhanced control of an established persistent viral infection. Thus, combinatorial blockade of multiple immune-regulatory molecules may ultimately restore the T-cell responses required to tip the balance from viral persistence to immune-mediated control or elimination of persistent infection.},
	keywords = {Animals, Antibodies, Antigens, CD, Antigens, CD274, Drug Therapy, Combination, Immunity, Immunotherapy, Interleukin-10, Mice, Mice, Inbred C57BL, Signal Transduction, T-Lymphocytes, Virus Diseases},
	issn = {1091-6490},
	doi = {10.1073/pnas.0811139106},
	author = {Brooks, David G and Ha, Sang-Jun and Elsaesser, Heidi and Sharpe, Arlene H and Freeman, Gordon J and Oldstone, Michael B A}
}
@article {542396,
	title = {Interaction of human PD-L1 and B7-1.},
	journal = {Mol Immunol},
	volume = {45},
	number = {13},
	year = {2008},
	month = {2008 Aug},
	pages = {3567-72},
	abstract = {Numerous studies have pointed to the role of programmed death-1 ligand 1 (PD-L1) in regulating tolerance, chronic infection, and tumor immunity. Recently, we have identified murine B7-1 as a new binding partner for murine PD-L1. Human and mouse B7-1 share only 46\% identity, leading us to question whether human B7-1 and PD-L1 can participate in a similar interaction. Here we show that human B7-1 can interact with human PD-L1 with affinity greater than that of B7-1 with CD28, but less than that of B7-1 with CTLA-4 or of PD-L1 with PD-1. We characterize a series of anti-human PD-L1 monoclonal antibodies and identify antibodies that can block interactions of PD-L1 with B7-1, PD-1, or both. Since PD-L1 and CD28 on T cells may compete for B7-1 as a binding partner and CD8 T cells may express high or low levels of CD28, we examined when PD-L1 and CD28 are co-expressed on CD8 T cells. We compared the time-course and extent of PD-L1 induction on CD8 CD28high versus CD28low T cells following stimulation with anti-CD3. We show that PD-L1 is induced to a higher level on CD28high T cells than on CD28low T cells upon activation. These results suggest that PD-L1 may play an important and undervalued role on human T cells.},
	keywords = {Animals, Antibodies, Monoclonal, Antigens, CD, Antigens, CD274, Antigens, CD28, Antigens, CD80, Cells, Cultured, Humans, Lymphocyte Activation, Mice, Protein Binding, T-Lymphocytes},
	issn = {0161-5890},
	doi = {10.1016/j.molimm.2008.05.014},
	author = {Butte, Manish J and Pe{\~n}a-Cruz, Victor and Kim, Mi-Jung and Freeman, Gordon J and Sharpe, Arlene H}
}
@article {542391,
	title = {Intrafollicular location of marginal zone/CD1d(hi) B cells is associated with autoimmune pathology in a mouse model of lupus.},
	journal = {Lab Invest},
	volume = {88},
	number = {9},
	year = {2008},
	month = {2008 Sep},
	pages = {1008-20},
	abstract = {Marginal zone (MZ) B cells contain a large number of autoreactive clones and the expansion of this compartment has been associated with autoimmunity. MZ B cells also efficiently transport blood-borne antigen to the follicles where they activate T cells and differentiate into plasma cells. Using the B6.NZM2410.Sle1.Sle2.Sle3 (B6.TC) model of lupus, we show that the IgM+ CD1d(hi)/MZ B-cell compartment is expanded, and a large number of them reside inside the follicles. Contrary to the peripheral B-cell subset distribution and their activation status, the intrafollicular location of B6.TC IgM+ CD1d(hi)/MZ B cells depends on both bone marrow- and stromal-derived factors. Among the factors responsible for this intrafollicular location, we have identified an increased response to CXCL13 by B6.TC MZ B cells and a decreased expression of VCAM-1 on stromal cells in the B6.TC MZ. However, the reduced number of MZ macrophages observed in B6.TC MZs was independent of the IgM+ CD1d(hi)/B-cell location. B7-2 but not B7-1 deficiency restored IgM+ CD1d(hi)/MZ B-cell follicular exclusion in B6.TC mice, and it correlated with tolerance to dsDNA and a significant reduction of autoimmune pathology. These results suggest that follicular exclusion of IgM+ CD1d(hi)/MZ B cells is an important B-cell tolerance mechanism, and that B7-2 signaling is involved in breaching this tolerance checkpoint.},
	keywords = {Animals, Antigens, CD1, B-Lymphocytes, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Fluorescent Antibody Technique, Lupus Erythematosus, Systemic, Mice, Mice, Inbred C57BL},
	issn = {1530-0307},
	doi = {10.1038/labinvest.2008.62},
	author = {Duan, Biyan and Niu, Haitao and Xu, Zhiwei and Sharpe, Arlene H and Croker, Byron P and Sobel, Eric S and Morel, Laurence}
}
@article {542381,
	title = {Programmed death ligand 1 regulates a critical checkpoint for autoimmune myocarditis and pneumonitis in MRL mice.},
	journal = {J Immunol},
	volume = {181},
	number = {4},
	year = {2008},
	month = {2008 Aug 15},
	pages = {2513-21},
	abstract = {MRL/MpJ-Fas(lpr) (MRL-Fas(lpr)) mice develop a spontaneous T cell and macrophage-dependent autoimmune disease that shares features with human lupus. Interactions via the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway down-regulate immune responses and provide a negative regulatory checkpoint in mediating tolerance and autoimmune disease. Therefore, we tested the hypothesis that the PD-1/PD-L1 pathway suppresses lupus nephritis and the systemic illness in MRL-Fas(lpr) mice. For this purpose, we compared kidney and systemic illness (lymph nodes, spleen, skin, lung, glands) in PD-L1 null (-/-) and PD-L1 intact (wild type, WT) MRL-Fas(lpr) mice. Unexpectedly, PD-L1(-/-);MRL-Fas(lpr) mice died as a result of autoimmune myocarditis and pneumonitis before developing renal disease or the systemic illness. Dense infiltrates, consisting of macrophage and T cells (CD8(+) > CD4(+)), were prominent throughout the heart (atria and ventricles) and localized specifically around vessels in the lung. In addition, once disease was evident, we detected heart specific autoantibodies in PD-L1(-/-);MRL-Fas(lpr) mice. This unique phenotype is dependent on MRL-specific background genes as PD-L1(-/-);MRL(+/+) mice lacking the Fas(lpr) mutation developed autoimmune myocarditis and pneumonitis. Notably, the transfer of PD-L1(-/-);MRL(+/+) bone marrow cells induced myocarditis and pneumonitis in WT;MRL(+/+) mice, despite a dramatic up-regulation of PD-L1 expression on endothelial cells in the heart and lung of WT;MRL(+/+) mice. Taken together, we suggest that PD-L1 expression is central to autoimmune heart and lung disease in lupus-susceptible (MRL) mice.},
	keywords = {Animals, Antigens, CD274, Antigens, CD80, Antigens, CD95, Antigens, Surface, Apoptosis Regulatory Proteins, Autoimmune Diseases, Bone Marrow Transplantation, Female, Genetic Predisposition to Disease, Immunophenotyping, Lupus Erythematosus, Systemic, Male, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Inbred MRL lpr, Mice, Knockout, Mice, Transgenic, Myocarditis, Peptides, Pneumonia, Programmed Cell Death 1 Receptor, Radiation Chimera, Signal Transduction},
	issn = {1550-6606},
	author = {Lucas, Julie A and Menke, Julia and Rabacal, Whitney A and Schoen, Frederick J and Sharpe, Arlene H and Kelley, Vicki R}
}
@article {542376,
	title = {T-cell costimulation and coinhibition in atherosclerosis.},
	journal = {Circ Res},
	volume = {103},
	number = {11},
	year = {2008},
	month = {2008 Nov 21},
	pages = {1220-31},
	abstract = {Evidence from many human and rodent studies has established that T lymphocytes enhance inflammation in atherosclerotic plaques and contribute to lesion progression and remodeling. Recent work also indicates that regulatory T cells are important in limiting proatherogenic T-cell responses. Given the important role of T cells in atherosclerosis, there is a need to fully understand how proatherogenic T cells are activated and regulated. Antigen-dependent activation of na{\"\i}ve T cells, leading to clonal expansion and effector T-cell differentiation, and effector and memory T cells, is enhanced by signals provided by costimulatory molecules expressed by antigen presenting cells, which bind to receptors on the T cells. In addition, T-cell responses to antigen are negatively regulated by coinhibitory molecules expressed by antigen-presenting cells, which bind to receptors on T cells. Two major families of costimulatory molecules include the B7 and the tumor necrosis factor (TNF) families. These molecules bind to receptors on T cells belonging to the CD28 or TNF receptor families, respectively. The best-defined coinhibitors and their receptors belong to the B7 and CD28 families. Recent work has begun to define how these T-cell costimulatory and coinhibitory pathways influence atherosclerosis, largely in mouse models of the disease. Profound effects are attributable to molecules in both the B7/CD28 (B7-1/2, ICOS, and PDL-1/2) and the TNF/TNF receptor (CD40, OX40, and CD137) families. One emerging theme is that both pathogenic effector T-cell responses and regulatory T cells are influenced by overlapping sets of costimulators and coinhibitors. These complexities must be considered as immunotherapeutic approaches for atherosclerotic disease are developed.},
	keywords = {Animals, Antigens, CD, Antigens, CD28, Atherosclerosis, CD40 Ligand, Cell Differentiation, Humans, Immunologic Memory, Immunotherapy, Lymphocyte Activation, Major Histocompatibility Complex, Mice, Models, Animal, Receptors, Antigen, T-Cell, T-Lymphocytes, T-Lymphocytes, Regulatory, Tumor Necrosis Factor-alpha},
	issn = {1524-4571},
	doi = {10.1161/CIRCRESAHA.108.182428},
	author = {Gotsman, Israel and Sharpe, Arlene H and Lichtman, Andrew H}
}
@article {542386,
	title = {TLR agonists regulate alloresponses and uncover a critical role for donor APCs in allogeneic bone marrow rejection.},
	journal = {Blood},
	volume = {112},
	number = {8},
	year = {2008},
	month = {2008 Oct 15},
	pages = {3508-16},
	abstract = {Cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpG ODNs) are synthetic ODNs with unmethylated DNA sequences that mimic viral and bacterial DNA and protect against infectious agents and tumor challenge. We show that CpG ODNs markedly accelerated graft-versus-host disease (GVHD) lethality by Toll-like receptor 9 (TLR9) ligation of host antigen-presenting cells (APCs), dependent upon host IFNgamma but independent of host IL-12, IL-6, or natural killer (NK) cells. Imaging studies showed significantly more green fluorescent protein-positive (GFP(+)) effector T cells in lymphoid and nonlymphoid organs. In engraftment studies, CpG ODNs promoted allogeneic donor bone marrow (BM) rejection independent of host IFNgamma, IL-12, or IL-6. During the course of these studies, we uncovered a previously unknown and critical role of donor BM APCs in modulating the rejection response. CpG ODNs promoted BM rejection by ligation of donor BM, but not host, TLR9. CpG ODNs did not impair engraftment of TLR9(-/-) BM unless wild-type myeloid (CD11b(+)) but not B-lineage (CD19(+)) BM cells were added to the donor inoculum. The importance of donor BM APCs in modulating the strength of the host antidonor rejection response was underscored by the finding that B7-1/B7-2(-/-) BM was less likely than wild-type BM to be rejected. Collectively, these data offer new insight into the mechanism of alloresponses regulating GVHD and BM rejection.},
	keywords = {Animals, Antigen-Presenting Cells, Bone Marrow Cells, Bone Marrow Transplantation, Graft vs Host Disease, Immune System, Interferon-gamma, Interleukin-12, Interleukin-6, Killer Cells, Natural, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Toll-Like Receptors, Transplantation, Homologous, Treatment Outcome},
	issn = {1528-0020},
	doi = {10.1182/blood-2007-09-113670},
	author = {Taylor, Patricia A and Ehrhardt, Michael J and Lees, Christopher J and Panoskaltsis-Mortari, Angela and Krieg, Arthur M and Sharpe, Arlene H and Murphy, William J and Serody, Jonathan S and Hemmi, Hiroaki and Akira, Shizuo and Levy, Robert B and Blazar, Bruce R}
}
@article {542466,
	title = {The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection.},
	journal = {Nat Immunol},
	volume = {8},
	number = {3},
	year = {2007},
	month = {2007 Mar},
	pages = {239-45},
	abstract = {The programmed cell death 1 (PD-1) surface receptor binds to two ligands, PD-L1 and PD-L2. Studies have shown that PD-1-PD-L interactions control the induction and maintenance of peripheral T cell tolerance and indicate a previously unknown function for PD-L1 on nonhematopoietic cells in protecting tissues from autoimmune attack. PD-1 and its ligands have also been exploited by a variety of microorganisms to attenuate antimicrobial immunity and facilitate chronic infection. Here we examine the functions of PD-1 and its ligands in regulating antimicrobial and self-reactive T cell responses and discuss the therapeutic potential of manipulating this pathway.},
	keywords = {Animals, Antigens, CD, Antigens, CD274, Autoimmunity, Communicable Diseases, Humans, Immune Tolerance, Intercellular Signaling Peptides and Proteins, Lymphocyte Activation, Models, Immunological, Programmed Cell Death 1 Ligand 2 Protein},
	issn = {1529-2908},
	doi = {10.1038/ni1443},
	author = {Sharpe, Arlene H and Wherry, E John and Ahmed, Rafi and Freeman, Gordon J}
}
@article {542461,
	title = {PD-1 and its ligands in T-cell immunity.},
	journal = {Curr Opin Immunol},
	volume = {19},
	number = {3},
	year = {2007},
	month = {2007 Jun},
	pages = {309-14},
	abstract = {The past year has seen significant advances in our understanding of the critical roles of negative immunoregulatory signals delivered by the programmed death 1 (PD-1)-PD-1 ligand (PD-L) pathway in regulating T-cell activation and tolerance. Emerging evidence indicates that PD-Ls play an essential role on dendritic cells (DCs), both directly during DC-T cell interactions and indirectly through signaling into the DC. Recent studies point to a novel role for PD-L1 in maintaining tissue tolerance. Finally, PD-1 has recently been shown to be highly expressed on exhausted T cells during chronic viral infection, and blockade of PD-1 or PD-L1 can revive exhausted T cells, enabling them to proliferate and produce effector cytokines.},
	keywords = {Animals, Antigens, CD, Antigens, CD274, Apoptosis Regulatory Proteins, Cell Communication, Dendritic Cells, Humans, Immune Tolerance, Lymphocyte Activation, Programmed Cell Death 1 Receptor, T-Lymphocytes},
	issn = {0952-7915},
	doi = {10.1016/j.coi.2007.04.012},
	author = {Keir, Mary E and Francisco, Loise M and Sharpe, Arlene H}
}
@article {542456,
	title = {Development of autoimmunity in mice lacking DNA topoisomerase 3beta.},
	journal = {Proc Natl Acad Sci U S A},
	volume = {104},
	number = {22},
	year = {2007},
	month = {2007 May 29},
	pages = {9242-7},
	abstract = {Mice lacking DNA topoisomerase 3beta are predisposed to a shortened lifespan, infertility, and lesions in multiple organs resulting from inflammatory responses. Examination of the immune system of 6- and 52-week-old top3beta(-/-) mice revealed no significant aberrations in their central and peripheral tolerance or in T lymphocyte activation. However, the older but not the younger cohort shows a high incidence of serum autoantibodies relative to their TOP3beta(+/+) age-mates. The mutant mice also show an increase in numerical aberrations of chromosomes in splenocytes and bone marrow cells, as well as an increase in apoptotic cells in the thymus. Thus, it appears plausible that the inflammatory lesions in top3beta(-/-) mice are caused by the development of autoimmunity as they age: Chromosomal abnormalities in top3beta(-/-) mice might lead to a persistent increase in apoptotic cells, which might in turn lead to the progression of autoimmunity.},
	keywords = {Animals, Apoptosis, Autoantibodies, Autoimmunity, Cell Proliferation, Chromosome Deletion, Chromosomes, Mammalian, DNA Topoisomerases, Type I, Immune System, Mice, Mice, Knockout},
	issn = {0027-8424},
	doi = {10.1073/pnas.0703587104},
	author = {Kwan, Kelvin Y and Greenwald, Rebecca J and Mohanty, Subhasis and Sharpe, Arlene H and Shaw, Albert C and Wang, James C}
}
@article {542426,
	title = {Endothelial programmed death-1 ligand 1 (PD-L1) regulates CD8+ T-cell mediated injury in the heart.},
	journal = {Circulation},
	volume = {116},
	number = {18},
	year = {2007},
	month = {2007 Oct 30},
	pages = {2062-71},
	abstract = {BACKGROUND: PD-L1 and PD-L2 are ligands for the inhibitory receptor programmed death-1 (PD-1), which is an important regulator of immune responses. PD-L1 is induced on cardiac endothelial cells under inflammatory conditions, but little is known about its role in regulating immune injury in the heart.

METHODS AND RESULTS: Cytotoxic T-lymphocyte-mediated myocarditis was induced in mice, and the influence of PD-L1 signaling was studied with PD-L1/L2-deficient mice and blocking antibodies. During cytotoxic T-lymphocyte-induced myocarditis, the upregulation of PD-L1 on cardiac endothelia was dependent on T-cell-derived interferon-gamma, and blocking of interferon-gamma signaling worsened disease. Genetic deletion of both PD-1 ligands [PD-L1/2(-/-)], as well as treatment with PD-L1 blocking antibody, transformed transient myocarditis to lethal disease, in association with widespread polymorphonuclear leukocyte-rich microabscesses but without change in cytotoxic T-lymphocyte recruitment. PD-L1/2(-/-) mice reconstituted with bone marrow from wild-type mice remained susceptible to severe disease, which demonstrates that PD-L1 on non-bone marrow-derived cells confers the protective effect. Finally, depletion of polymorphonuclear leukocytes reversed the enhanced susceptibility to lethal myocarditis attributable to PD-L1 deficiency.

CONCLUSIONS: Myocardial PD-L1, mainly localized on endothelium, is critical for control of immune-mediated cardiac injury and polymorphonuclear leukocyte inflammation.},
	keywords = {Animals, Antigens, CD274, Antigens, CD80, CD8-Positive T-Lymphocytes, Endothelial Cells, Inflammation, Inflammation Mediators, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Myocarditis, Neutrophils, Peptides, Signal Transduction},
	issn = {1524-4539},
	doi = {10.1161/CIRCULATIONAHA.107.709360},
	author = {Grabie, Nir and Gotsman, Israel and DaCosta, Rosa and Pang, Hong and Stavrakis, George and Butte, Manish J and Keir, Mary E and Freeman, Gordon J and Sharpe, Arlene H and Lichtman, Andrew H}
}
@article {542441,
	title = {The function of donor versus recipient programmed death-ligand 1 in corneal allograft survival.},
	journal = {J Immunol},
	volume = {179},
	number = {6},
	year = {2007},
	month = {2007 Sep 15},
	pages = {3672-9},
	abstract = {Programmed death-ligand (PD-L)1 and PD-L2, newer B7 superfamily members, are implicated in the negative regulation of immune responses and peripheral tolerance. To examine their function in alloimmunity, we used the murine model of orthotopic corneal transplantation. We demonstrate that PD-L1, but not PD-L2, is constitutively expressed at high levels by the corneal epithelial cells, and at low levels by corneal CD45+ cells in the stroma, whereas it is undetectable on stromal fibroblasts and corneal endothelial cells. Inflammation induces PD-L1 up-regulation by corneal epithelial cells, and infiltration of significant numbers of PD-L1+CD45+CD11b+ cells. Blockade with anti-PD-L1 mAb dramatically enhances rejection of C57BL/6 corneal allografts by BALB/c recipients. To examine the selective contribution of donor vs host PD-L1 in modulating allorejection, we used PD-L1-/- mice as hosts or donors of combined MHC and minor H-mismatched corneal grafts. BALB/c grafts placed in PD-L1-/- C57BL/6 hosts resulted in pronounced T cell priming in the draining lymph nodes, and universally underwent rapid rejection. Allografts from PD-L1-/- C57BL/6 donors were also significantly more susceptible to rejection than wild-type C57BL/6 grafts placed into BALB/c hosts, primarily as a result of increased T cell infiltration rather than enhanced priming. Taken together, our results identify differential roles for recipient vs donor PD-L1 in regulating induction vs effector of alloimmunity in corneal grafts, the most common form of tissue transplantation, and highlight the importance of peripheral tissue-derived PD-L1 in down-regulating local immune responses.},
	keywords = {Animals, Antigens, CD274, Antigens, CD45, Antigens, CD80, Cell Movement, Cornea, Corneal Transplantation, Down-Regulation, Graft Enhancement, Immunologic, Graft Survival, Immune Tolerance, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Peptides, T-Lymphocyte Subsets, Tissue Donors},
	issn = {0022-1767},
	author = {Shen, Linling and Jin, Yiping and Freeman, Gordon J and Sharpe, Arlene H and Dana, M Reza}
}
@article {542446,
	title = {Induction of autoimmune disease in CTLA-4-/- mice depends on a specific CD28 motif that is required for in vivo costimulation.},
	journal = {Proc Natl Acad Sci U S A},
	volume = {104},
	number = {34},
	year = {2007},
	month = {2007 Aug 21},
	pages = {13756-61},
	abstract = {CTLA-4-deficient mice develop a lethal autoimmune lymphoproliferative disorder that is strictly dependent on in vivo CD28 costimulation. Nevertheless, it is not known whether there is a specific site on the CD28 molecule that is required for induction of autoimmunity. Using CTLA-4-deficient mice expressing CD28 molecules with various point mutations in the CD28 cytosolic tail, the present study documents that in vivo costimulation for induction of autoimmune disease strictly requires an intact C-terminal proline motif that promotes lymphocyte-specific protein tyrosine kinase Lck binding to the CD28 cytosolic tail, because point mutations in C-terminal proline residues (Pro-187 and Pro-190) completely prevented disease induction. In contrast, in vivo costimulation for disease induction did not require either an intact YMNM motif or an intact N-terminal proline motif, which, respectively, promote phosphoinositide 3-kinase and IL2-inducible T cell kinase binding to the CD28 cytosolic tail. Thus, in vivo CD28 costimulation for induction of autoimmune disease is strictly and specifically dependent on an intact C-terminal proline motif that serves as a lymphocyte-specific protein tyrosine Lck kinase binding site in the CD28 cytosolic tail.},
	keywords = {Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Antigens, CD, Antigens, CD28, Antigens, Differentiation, Autoimmune Diseases, Binding Sites, CTLA-4 Antigen, Mice, Mice, Knockout, Molecular Sequence Data, Sequence Alignment, Sequence Homology, Amino Acid, Survival Rate},
	issn = {0027-8424},
	doi = {10.1073/pnas.0706509104},
	author = {Tai, Xuguang and Van Laethem, Francois and Sharpe, Arlene H and Singer, Alfred}
}
@article {542431,
	title = {PD-1 regulates self-reactive CD8+ T cell responses to antigen in lymph nodes and tissues.},
	journal = {J Immunol},
	volume = {179},
	number = {8},
	year = {2007},
	month = {2007 Oct 15},
	pages = {5064-70},
	abstract = {PD-1, an inhibitory receptor expressed on activated lymphocytes, regulates tolerance and autoimmunity. We tested the role of PD-1:PD-1 ligand (PD-L) interactions in cross-presentation and the generation and control of CD8(+) responses against self-Ag. Ag-naive PD-1(-/-) OVA-specific OT-I CD8(+) T cells exhibited exacerbated responses to cross-presented Ag in mice expressing soluble OVA under the control of the rat insulin promoter (RIP-ova(high)). Following adoptive transfer into RIP-ova(high) recipients, PD-1(-/-) OT-I T cells expanded in the pancreatic lymph node. In contrast to wild-type OT-I cells, PD-1(-/-) OT-I T cells secreted IFN-gamma and migrated into the pancreas, ultimately causing diabetes. Loss of PD-1 affected CD8(+) cells intrinsically, and did not significantly alter the responses of wild-type OT-I T cells adoptively transferred into the same RIP-ova(high) recipient mouse. PD-1:PD-L interactions also limited CD8(+) effector cells, and PD-L1 expression on parenchymal tissues protected against effector OT-I T cell attack. Finally, we found that the loss of PD-1 on effector OT-I cells lowers the threshold for Ag recognition in peripheral tissues. These findings indicate two checkpoints where PD-1 attenuates self-reactive T cell responses: presentation of self-Ag to naive self-reactive T cells by dendritic cells in the draining lymph node and reactivation of pathogenic self-reactive T cells in the target organ.},
	keywords = {Animals, Antigens, Antigens, CD274, Antigens, CD80, Antigens, Surface, Apoptosis Regulatory Proteins, CD8-Positive T-Lymphocytes, Cell Line, Cross-Priming, Lymph Nodes, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Ovalbumin, Pancreas, Peptides, Programmed Cell Death 1 Receptor, Self Tolerance},
	issn = {0022-1767},
	author = {Keir, Mary E and Freeman, Gordon J and Sharpe, Arlene H}
}
@article {542421,
	title = {Programmed death 1 ligand (PD-L) 1 and PD-L2 limit autoimmune kidney disease: distinct roles.},
	journal = {J Immunol},
	volume = {179},
	number = {11},
	year = {2007},
	month = {2007 Dec 1},
	pages = {7466-77},
	abstract = {The programmed death 1/programmed death 1 ligand (PD-L) pathway is instrumental in peripheral tolerance. Blocking this pathway exacerbates experimental autoimmune diseases, but its role in autoimmune kidney disease has not been explored. Therefore, we tested the hypothesis that the programmed death 1 ligands (PD-L1 and PD-L2), provide a protective barrier during T cell- and macrophage (Mphi)-dependent autoimmune kidney disease. For this purpose, we compared nephrotoxic serum nephritis (NSN) in mice lacking PD-L1 (PD-L1(-/-)), PD-L2 (PD-L2(-/-)), or both (PD-L1/L2(-/-)) to wild-type (WT) C57BL/6 mice. Kidney pathology, loss of renal function, and intrarenal leukocyte infiltrates were increased in each PD-L(-/-) strain as compared with WT mice. Although the magnitude of renal pathology was similar in PD-L1(-/-) and PD-L2(-/-) mice, our findings suggest that kidney disease in each strain is regulated by distinct mechanisms. Specifically, we detected increased CD68(+) cells along with elevated circulating IgG and IgG deposits in glomeruli in PD-L2(-/-) mice, but not PD-L1(-/-) mice. In contrast, we detected a rise in activated CD8(+) T cells in PD-L1(-/-) mice, but not PD-L2(-/-) mice. Furthermore, since PD-L1 is expressed by parenchymal and hemopoietic cells in WT kidneys, we explored the differential impact of PD-L1 expression on these cell types by inducing NSN in bone marrow chimeric mice. Our results indicate that PD-L1 expression on hemopoietic cells, and not parenchymal cells, is primarily responsible for limiting leukocyte infiltration during NSN. Taken together, our findings indicate that PD-L1 and PD-L2 provide distinct negative regulatory checkpoints poised to suppress autoimmune renal disease.},
	keywords = {Animals, Antigens, CD274, Antigens, CD80, Apoptosis, Autoimmune Diseases, Down-Regulation, Gene Expression Profiling, Immune Sera, Kidney Diseases, Macrophages, Male, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Nephritis, Peptides, Programmed Cell Death 1 Ligand 2 Protein, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, T-Lymphocytes},
	issn = {0022-1767},
	author = {Menke, Julia and Lucas, Julie A and Zeller, Geraldine C and Keir, Mary E and Huang, Xiao R and Tsuboi, Naotake and Mayadas, Tanya N and Lan, Han Y and Sharpe, Arlene H and Kelley, Vicki R}
}
@article {542451,
	title = {Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses.},
	journal = {Immunity},
	volume = {27},
	number = {1},
	year = {2007},
	month = {2007 Jul},
	pages = {111-22},
	abstract = {Pathways in the B7:CD28 family of costimulatory molecules regulate T cell activation and tolerance. B7-dependent responses in Cd28(-/-)Ctla4(-/-) T cells together with reports of stimulatory and inhibitory functions for Programmed Death-1 Ligand 1 or 2 molecules (PD-L1 or PD-L2) have suggested additional receptors for these B7 family members. We show that B7-1 and PD-L1 interacted with affinity intermediate to that of B7-1:CD28 and B7-1:CTLA-4. The PD-L1:B7-1 interface overlapped with the B7-1:CTLA-4 and PD-L1:PD-1 (Programmed Death-1) interfaces. T cell activation and cytokine production were inhibited by the interaction of B7-1 with PD-L1. The responses of PD-1-deficient versus PD-1,B7-1 double-deficient T cells to PD-L1 and of CD28,CTLA-4 double-deficient versus CD28,CTLA-4,PD-L1 triple-deficient T cells to B7-1 demonstrated that PD-L1 and B7-1 interact specifically to inhibit T cell activation. Our findings point to a substantial bidirectional inhibitory interaction between B7-1 and PD-L1 and add an additional dimension to immunoregulatory functions of the B7:CD28 family.},
	keywords = {Animals, Antigens, CD274, Antigens, CD80, Cell Line, Cell Proliferation, Cells, Cultured, Cercopithecus aethiops, COS Cells, Cytokines, Down-Regulation, Humans, Ligands, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Peptides, Protein Binding, T-Lymphocytes},
	issn = {1074-7613},
	doi = {10.1016/j.immuni.2007.05.016},
	author = {Butte, Manish J and Keir, Mary E and Phamduy, Theresa B and Sharpe, Arlene H and Freeman, Gordon J}
}
@article {542416,
	title = {TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells.},
	journal = {Immunity},
	volume = {27},
	number = {6},
	year = {2007},
	month = {2007 Dec},
	pages = {927-40},
	abstract = {The T cell immunoglobulin mucin (TIM) proteins regulate T cell activation and tolerance. Here we showed that TIM-4 is expressed on human and mouse macrophages and dendritic cells, and both TIM-4 and TIM-1 specifically bound phosphatidylserine (PS) on the surface of apoptotic cells but not any other phospholipid tested. TIM-4(+) peritoneal macrophages, TIM-1(+) kidney cells, and TIM-4- or TIM-1-transfected cells efficiently phagocytosed apoptotic cells, and phagocytosis could be blocked by TIM-4 or TIM-1 monoclonal antibodies. Mutations in the unique cavity of TIM-4 eliminated PS binding and phagocytosis. TIM-4 mAbs that blocked PS binding and phagocytosis mapped to epitopes in this binding cavity. These results show that TIM-4 and TIM-1 are immunologically restricted members of the group of receptors whose recognition of PS is critical for the efficient clearance of apoptotic cells and prevention of autoimmunity.},
	keywords = {Animals, Apoptosis, Dendritic Cells, Humans, Lymphocyte Activation, Macrophages, Membrane Glycoproteins, Membrane Proteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, NIH 3T3 Cells, Phagocytosis, Phosphatidylserines, Receptors, Virus, T-Lymphocytes},
	issn = {1074-7613},
	doi = {10.1016/j.immuni.2007.11.011},
	author = {Kobayashi, Norimoto and Karisola, Piia and Pe{\~n}a-Cruz, Victor and Dorfman, David M and Jinushi, Masahisa and Umetsu, Sarah E and Butte, Manish J and Nagumo, Haruo and Chernova, Irene and Zhu, Baogong and Sharpe, Arlene H and Ito, Susumu and Dranoff, Glenn and Kaplan, Gerardo G and Casasnovas, Jose M and Umetsu, Dale T and DeKruyff, Rosemarie H and Freeman, Gordon J}
}
@article {542436,
	title = {Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection.},
	journal = {Proc Natl Acad Sci U S A},
	volume = {104},
	number = {39},
	year = {2007},
	month = {2007 Sep 25},
	pages = {15430-5},
	abstract = {Many chronic viral infections are marked by pathogen persistence and a generalized immunosuppression. The exact mechanisms by which this occurs are still unknown. Using a mouse model of persistent lymphocytic choriomeningitis virus (LCMV) infection, we demonstrate viral targeting of fibroblastic reticular cells (FRC) in the lymphoid organs. The FRC stromal networks are critical for proper lymphoid architecture and function. High numbers of FRC were infected by LCMV clone 13, which causes a chronic infection, whereas few were infected by the acute strain, LCMV Armstrong. The function of the FRC conduit network was altered after clone 13 infection by the action of CD8(+) T cells. Importantly, expression of the inhibitory programmed death ligand 1, which was up-regulated on FRC after infection, reduced early CD8(+) T cell-mediated immunopathology and prevented destruction of the FRC architecture in the spleen. Together, this reveals an important tropism during a persistent viral infection. These data also suggest that the inhibitory PD-1 pathway, which likely evolved to prevent excessive immunopathology, may contribute to viral persistence in FRC during chronic infection.},
	keywords = {Animals, CD8-Positive T-Lymphocytes, Chronic Disease, Fibroblasts, Immune Tolerance, Immunosuppression, Immunosuppressive Agents, Infection, Ligands, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Mice, Mice, Inbred C57BL, Microscopy, Electron, Transmission, Spleen},
	issn = {0027-8424},
	doi = {10.1073/pnas.0702579104},
	author = {Mueller, Scott N and Matloubian, Mehrdad and Clemens, Daniel M and Sharpe, Arlene H and Freeman, Gordon J and Gangappa, Shivaprakash and Larsen, Christian P and Ahmed, Rafi}
}
@article {542516,
	title = {Inducible co-stimulator null MRL-Faslpr mice: uncoupling of autoantibodies and T cell responses in lupus.},
	journal = {J Am Soc Nephrol},
	volume = {17},
	number = {1},
	year = {2006},
	month = {2006 Jan},
	pages = {122-30},
	abstract = {MRL/MpJ-Tnfrsf6lpr (MRL-Faslpr) mice develop a spontaneous T cell-dependent autoimmune disease that shares features with human lupus, including fatal nephritis, systemic pathology, and autoantibodies (autoAb). The inducible co-stimulator (ICOS) is upregulated on activated T cells and modulates T cell-mediated responses. To investigate whether ICOS has an essential role in regulating autoimmune lupus nephritis and the systemic illness in MRL-Faslpr mice, ICOS null (-/-) MRL Faslpr and ICOS intact (+/+) MRL-Faslpr strains (wild-type [WT]) were generated and compared. It was determined that in ICOS-/- MRL-Faslpr as compared with the WT strain, (1) there is a significant reduction in circulating IgG and double-stranded DNA autoantibody isotype titers, and (2) there is an amplification of the frequency of intrarenal T cells generating IFN-gamma and TNF-alpha in ICOS-/- versus WT mice. Of note, eliminating ICOS in the MRL-Faslpr strain does not alter renal pathology or function. Despite the reduction in circulating IgG and autoantibody isotypes (G1, G2a, and G2b), the amount of these IgG isotypes depositing in kidneys is similar. Furthermore, the systemic illness (skin, salivary and lacrimal glands, lungs, lymphadenopathy, and splenomegaly) is equivalent in ICOS-/- MRL-Faslpr and WT mice. These findings highlight the danger of relying on individual parameters, such as quantitative serum Ig levels and T cell functions, as prognostic indicators of lupus.},
	keywords = {Animals, Antigens, Differentiation, T-Lymphocyte, Autoantibodies, Blood Urea Nitrogen, Immunoglobulin G, Inducible T-Cell Co-Stimulator Protein, Interferon-gamma, Interleukin-10, Interleukin-4, Lupus Nephritis, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Inbred MRL lpr, Proteinuria, T-Lymphocytes, Tumor Necrosis Factor-alpha},
	issn = {1046-6673},
	doi = {10.1681/ASN.2005080802},
	author = {Zeller, Geraldine C and Hirahashi, Junichi and Schwarting, Andreas and Sharpe, Arlene H and Kelley, Vicki R}
}
@article {542541,
	title = {Requirement of homotypic NK-cell interactions through 2B4(CD244)/CD48 in the generation of NK effector functions.},
	journal = {Blood},
	volume = {107},
	number = {8},
	year = {2006},
	month = {2006 Apr 15},
	pages = {3181-8},
	abstract = {2B4 belongs to the CD2 subset of the IgG family of receptors. Members in this family have been shown to function as coreceptors via homophilic or heterophilic interactions. Both 2B4 and CD2 bind to CD48, another member of this family. Because all 3 molecules are expressed on natural killer (NK) cells, it raises a possibility that the binding of 2B4 and CD2 to CD48 among NK cells may have functional consequences. Using specific monoclonal antibodies and gene-deficient NK cells, we found that 2B4/CD48, but not CD2/CD48, interaction is essential for IL-2-driven expansion and activation of murine NK cells. In the absence of 2B4/CD48 interaction, NK cytotoxicity and IFN-gamma secretion on tumor target exposure is severely impaired. Impaired activation of NK cells in 2B4-deficient mice was also demonstrated by poor NK-mediated clearance of syngeneic tumor cells in these mice. Functional impairment of NK cells in the absence of 2B4/CD48 interactions was accompanied by defective calcium signaling, suggesting that the early signaling pathway of NK receptors is inhibited. Finally, homotypic interactions among NK cells through 2B4/CD48 was visualized by specific localization of GFP-tagged 2B4 onto NK-NK conjugation sites. Thus, these data identify a novel mechanism whereby NK effector function is regulated via homotypic 2B4/CD48 interactions.},
	keywords = {Animals, Antigens, CD, Antigens, CD2, Calcium Signaling, Interferon-gamma, Interleukin-2, Killer Cells, Natural, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Knockout, Neoplasms, Receptors, Immunologic},
	issn = {0006-4971},
	doi = {10.1182/blood-2005-01-0185},
	author = {Lee, Kyung-Mi and Forman, John P and McNerney, Megan E and Stepp, Susan and Kuppireddi, Sumalatha and Guzior, Dustin and Latchman, Yvette E and Sayegh, Mohamed H and Yagita, Hideo and Park, Chul-Kyu and Oh, Seog Bae and W{\"u}lfing, Christoph and Schatzle, John and Mathew, Porunelloor A and Sharpe, Arlene H and Kumar, Vinay}
}
@article {542481,
	title = {Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo.},
	journal = {J Immunol},
	volume = {177},
	number = {7},
	year = {2006},
	month = {2006 Oct 1},
	pages = {4376-83},
	abstract = {Naturally occurring CD4+ regulatory T cells (T(R)) that express CD25 and the transcription factor FoxP3 play a key role in immune homeostasis, preventing immune pathological responses to self and foreign Ags. CTLA-4 is expressed by a high percentage of these cells, and is often considered as a marker for T(R) in experimental and clinical analysis. However, it has not yet been proven that CTLA-4 has a direct role in T(R) function. In this study, using a T cell-mediated colitis model, we demonstrate that anti-CTLA-4 mAb treatment inhibits T(R) function in vivo via direct effects on CTLA-4-expressing T(R), and not via hyperactivation of colitogenic effector T cells. Although anti-CTLA-4 mAb treatment completely inhibits T(R) function, it does not reduce T(R) numbers or their homing to the GALT, suggesting the Ab mediates its function by blockade of a signal required for T(R) activity. In contrast to the striking effect of the Ab, CTLA-4-deficient mice can produce functional T(R), suggesting that under some circumstances other immune regulatory mechanisms, including the production of IL-10, are able to compensate for the loss of the CTLA-4-mediated pathway. This study provides direct evidence that CTLA-4 has a specific, nonredundant role in the function of normal T(R). This role has to be taken into account when targeting CTLA-4 for therapeutic purposes, as such a strategy will not only boost effector T cell responses, but might also break T(R)-mediated self-tolerance.},
	keywords = {Animals, Antibodies, Monoclonal, Antigens, CD, Antigens, CD4, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, Colitis, CTLA-4 Antigen, Disease Models, Animal, Flow Cytometry, Intestines, Lymphoid Tissue, Mice, Mice, Inbred BALB C, Mice, Knockout, Receptors, Interleukin-2, T-Lymphocytes, Regulatory},
	issn = {0022-1767},
	author = {Read, Simon and Greenwald, Rebecca and Izcue, Ana and Robinson, Nicholas and Mandelbrot, Didier and Francisco, Loise and Sharpe, Arlene H and Powrie, Fiona}
}
@article {542471,
	title = {Impaired regulatory T-cell response and enhanced atherosclerosis in the absence of inducible costimulatory molecule.},
	journal = {Circulation},
	volume = {114},
	number = {19},
	year = {2006},
	month = {2006 Nov 7},
	pages = {2047-55},
	abstract = {BACKGROUND: T-cell-mediated immunity contributes to the pathogenesis of atherosclerosis, but little is known about how these responses are regulated. We explored the influence of the inducible costimulatory molecule (ICOS) on atherosclerosis and associated immune responses.

METHODS AND RESULTS: Bone marrow chimeras were generated by transplanting ICOS-deficient or wild-type bone marrow into irradiated atherosclerosis-prone, LDR receptor-deficient mice, and the chimeric mice were fed a high-cholesterol diet for 8 weeks. Compared with controls, mice transplanted with ICOS-deficient marrow had a 43\% increase in the atherosclerotic burden, and importantly, their lesions had a 3-fold increase in CD4+ T cells, as well as increased macrophage, smooth muscle cell, and collagen content. CD4+ T cells from ICOS-deficient chimeras proliferated more and secreted more interferon-gamma and tumor necrosis factor-alpha than T cells from control mice, which suggests a lack of regulation. FoxP3+ regulatory T cells (Treg) were found to constitutively express high ICOS levels, which suggests a role for ICOS in Treg function. ICOS-deficient mice had decreased numbers of FoxP3+ Treg and impaired in vitro Treg suppressive function compared with control mice.

CONCLUSIONS: ICOS has a key role in regulation of atherosclerosis, through its effect on regulatory T-cell responses.},
	keywords = {Animals, Antigens, Differentiation, T-Lymphocyte, Atherosclerosis, Cells, Cultured, Female, Inducible T-Cell Co-Stimulator Protein, Lymphocyte Depletion, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, T-Lymphocytes, Regulatory},
	issn = {1524-4539},
	doi = {10.1161/CIRCULATIONAHA.106.633263},
	author = {Gotsman, Israel and Grabie, Nir and Gupta, Rajat and DaCosta, Rosa and MacConmara, Malcolm and Lederer, James and Sukhova, Galina and Witztum, Joseph L and Sharpe, Arlene H and Lichtman, Andrew H}
}
@article {542501,
	title = {PD-L1 and PD-L2 have distinct roles in regulating host immunity to cutaneous leishmaniasis.},
	journal = {Eur J Immunol},
	volume = {36},
	number = {1},
	year = {2006},
	month = {2006 Jan},
	pages = {58-64},
	abstract = {To compare the roles of programmed death 1 ligand 1 (PD-L1) and PD-L2 in regulating immunity to infection, we investigated responses of mice lacking PD-L1 or PD-L2 to infection with Leishmania mexicana. PD-L1(-/-) and PD-L2(-/-) mice exhibited distinct disease outcomes following infection with L. mexicana. In comparison to susceptible WT mice, PD-L1(-/-) mice showed resistance to L. mexicana, as demonstrated by reduced growth of cutaneous lesions and parasite burden. In contrast, PD-L2(-/-) mice developed exacerbated disease with increased parasite burden. Host resistance to L. mexicana is partly associated with the development of a Th1 response and down-regulation of the Th2 response. Both PD-L1(-/-) and PD-L2(-/-) mice produced levels of IFN-gamma similar to WT mice. However, the development of IL-4-producing cells was reduced in PD-L1(-/-) mice, demonstrating a role for PD-L1 in regulating Th cell differentiation. This inadequate Th2 response may explain the increased resistance of PD-L1(-/-) mice. Although no alterations in Th1/Th2 skewing were observed in PD-L2(-/-) mice, PD-L2(-/-) mice exhibited a marked increase in L. mexicana-specific antibody production. Increased Leishmania-specific IgG production may suppress the healing response through FcgammaR ligation on macrophages. Taken together, our results demonstrate that PD-L1 and PD-L2 have distinct roles in regulating the immune response to L. mexicana.},
	keywords = {Animals, Antigens, CD274, Antigens, CD80, Blotting, Southern, Cell Differentiation, Enzyme-Linked Immunosorbent Assay, Female, Immunoglobulin G, Immunoglobulin M, Leishmania mexicana, Leishmaniasis, Cutaneous, Membrane Glycoproteins, Mice, Mice, Transgenic, Peptides, Programmed Cell Death 1 Ligand 2 Protein, Th1 Cells, Th2 Cells},
	issn = {0014-2980},
	doi = {10.1002/eji.200535458},
	author = {Liang, Spencer C and Greenwald, Rebecca J and Latchman, Yvette E and Rosas, Lucia and Satoskar, Abhay and Freeman, Gordon J and Sharpe, Arlene H}
}
@article {542476,
	title = {Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade.},
	journal = {J Exp Med},
	volume = {203},
	number = {10},
	year = {2006},
	month = {2006 Oct 2},
	pages = {2223-7},
	abstract = {The programmed death (PD)-1-PD-1 ligand (PD-L) pathway, which is part of the B7-CD28 family, consists of the PD-1 receptor and its two ligands PD-L1 and PD-L2. Engagement of PD-1 by its ligands inhibits immune responses, and recent work has shown that PD-1 is highly expressed on exhausted T cells during chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. Blockade of this pathway reinvigorates the exhausted T cells, allowing them to expand and produce effector cytokines, raising the issue of whether this pathway has been exploited by a variety of viruses during chronic infection. New studies now extend these observations to HIV infection and human disease.},
	keywords = {Animals, Antigens, CD274, Antigens, CD80, Arenaviridae Infections, Gene Expression Regulation, HIV Infections, Ligands, Lymphocytic choriomeningitis virus, Membrane Glycoproteins, Mice, Models, Immunological, Peptides, Signal Transduction, T-Lymphocytes},
	issn = {0022-1007},
	doi = {10.1084/jem.20061800},
	author = {Freeman, Gordon J and Wherry, E John and Ahmed, Rafi and Sharpe, Arlene H}
}
@article {542496,
	title = {Restoring function in exhausted CD8 T cells during chronic viral infection.},
	journal = {Nature},
	volume = {439},
	number = {7077},
	year = {2006},
	month = {2006 Feb 9},
	pages = {682-7},
	abstract = {Functional impairment of antigen-specific T cells is a defining characteristic of many chronic infections, but the underlying mechanisms of T-cell dysfunction are not well understood. To address this question, we analysed genes expressed in functionally impaired virus-specific CD8 T cells present in mice chronically infected with lymphocytic choriomeningitis virus (LCMV), and compared these with the gene profile of functional memory CD8 T cells. Here we report that PD-1 (programmed death 1; also known as Pdcd1) was selectively upregulated by the exhausted T cells, and that in vivo administration of antibodies that blocked the interaction of this inhibitory receptor with its ligand, PD-L1 (also known as B7-H1), enhanced T-cell responses. Notably, we found that even in persistently infected mice that were lacking CD4 T-cell help, blockade of the PD-1/PD-L1 inhibitory pathway had a beneficial effect on the {\textquoteright}helpless{\textquoteright} CD8 T cells, restoring their ability to undergo proliferation, secrete cytokines, kill infected cells and decrease viral load. Blockade of the CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitory pathway had no effect on either T-cell function or viral control. These studies identify a specific mechanism of T-cell exhaustion and define a potentially effective immunological strategy for the treatment of chronic viral infections.},
	keywords = {Animals, Antigens, CD, Antigens, CD274, Antigens, CD80, Antigens, Differentiation, Antigens, Surface, Apoptosis Regulatory Proteins, CD8-Positive T-Lymphocytes, Cell Proliferation, Chronic Disease, CTLA-4 Antigen, Gene Expression Regulation, Immune Tolerance, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Membrane Glycoproteins, Mice, Peptides, Programmed Cell Death 1 Receptor, Substrate Specificity, Virus Diseases},
	issn = {1476-4687},
	doi = {10.1038/nature04444},
	author = {Barber, Daniel L and Wherry, E John and Masopust, David and Zhu, Baogong and Allison, James P and Sharpe, Arlene H and Freeman, Gordon J and Ahmed, Rafi}
}
@article {542486,
	title = {T-cell costimulation--biology, therapeutic potential, and challenges.},
	journal = {N Engl J Med},
	volume = {355},
	number = {10},
	year = {2006},
	month = {2006 Sep 7},
	pages = {973-5},
	keywords = {Animals, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antigen-Presenting Cells, Antigens, CD28, Cytokines, Humans, Immune Tolerance, Lymphocyte Activation, Mice, Models, Animal, T-Lymphocytes},
	issn = {1533-4406},
	doi = {10.1056/NEJMp068087},
	author = {Sharpe, Arlene H and Abbas, Abul K}
}
@article {542491,
	title = {Tissue expression of PD-L1 mediates peripheral T cell tolerance.},
	journal = {J Exp Med},
	volume = {203},
	number = {4},
	year = {2006},
	month = {2006 Apr 17},
	pages = {883-95},
	abstract = {Programmed death 1 (PD-1), an inhibitory receptor expressed on activated lymphocytes, regulates tolerance and autoimmunity. PD-1 has two ligands: PD-1 ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal cells, including pancreatic islet cells; and PD-L2, which is restricted to macrophages and dendritic cells. To investigate whether PD-L1 and PD-L2 have synergistic or unique roles in regulating T cell activation and tolerance, we generated mice lacking PD-L1 and PD-L2 (PD-L1/PD-L2(-/-) mice) and compared them to mice lacking either PD-L. PD-L1 and PD-L2 have overlapping functions in inhibiting interleukin-2 and interferon-gamma production during T cell activation. However, PD-L1 has a unique and critical role in controlling self-reactive T cells in the pancreas. Our studies with bone marrow chimeras demonstrate that PD-L1/PD-L2 expression only on antigen-presenting cells is insufficient to prevent the early onset diabetes that develops in PD-L1/PD-L2(-/-) non-obese diabetic mice. PD-L1 expression in islets protects against immunopathology after transplantation of syngeneic islets into diabetic recipients. PD-L1 inhibits pathogenic self-reactive CD4+ T cell-mediated tissue destruction and effector cytokine production. These data provide evidence that PD-L1 expression on parenchymal cells rather than hematopoietic cells protects against autoimmune diabetes and point to a novel role for PD-1-PD-L1 interactions in mediating tissue tolerance.},
	keywords = {Animals, Antigens, CD274, Antigens, CD80, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cells, Cultured, Cytokines, Diabetes Mellitus, Type 1, Hematopoietic Stem Cells, Immune Tolerance, Interferon-gamma, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Organ Specificity, Peptides, Programmed Cell Death 1 Ligand 2 Protein, T-Lymphocytes},
	issn = {0022-1007},
	doi = {10.1084/jem.20051776},
	author = {Keir, Mary E and Liang, Spencer C and Guleria, Indira and Latchman, Yvette E and Qipo, Andi and Albacker, Lee A and Koulmanda, Maria and Freeman, Gordon J and Sayegh, Mohamed H and Sharpe, Arlene H}
}
@article {542566,
	title = {CD70 signaling is critical for CD28-independent CD8+ T cell-mediated alloimmune responses in vivo.},
	journal = {J Immunol},
	volume = {174},
	number = {3},
	year = {2005},
	month = {2005 Feb 1},
	pages = {1357-64},
	abstract = {The inability to reproducibly induce robust and durable transplant tolerance using CD28-B7 pathway blockade is in part related to the persistence of alloreactive effector/memory CD8(+) T cells that are less dependent on this pathway for their cellular activation. We studied the role of the novel T cell costimulatory pathway, CD27-CD70, in alloimmunity in the presence and absence of CD28-B7 signaling. CD70 blockade prolonged survival of fully mismatched vascularized cardiac allografts in wild-type murine recipients, and in CD28-deficient mice induced long-term survival while significantly preventing the development of chronic allograft vasculopathy. CD70 blockade had little effect on CD4(+) T cell function but prevented CD8(+) T cell-mediated rejection, inhibited the proliferation and activation of effector CD8(+) T cells, and diminished the expansion of effector and memory CD8(+) T cells in vivo. Thus, the CD27-CD70 pathway is critical for CD28-independent effector/memory CD8(+) alloreactive T cell activation in vivo. These novel findings have important implications for the development of transplantation tolerance-inducing strategies in primates and humans, in which CD8(+) T cell depletion is currently mandatory.},
	keywords = {Acute Disease, Adoptive Transfer, Animals, Antibodies, Blocking, Antibodies, Monoclonal, Antigens, CD, Antigens, CD27, Antigens, CD28, Antigens, CD70, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Chronic Disease, Down-Regulation, Graft Rejection, Graft Survival, Heart Transplantation, Immunologic Memory, Isoantibodies, Killer Cells, Natural, Lymphocyte Activation, Membrane Proteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Mice, Transgenic, Signal Transduction, T-Lymphocytes, Cytotoxic, Th1 Cells, Th2 Cells, Transplantation, Heterotopic, Up-Regulation},
	issn = {0022-1767},
	author = {Yamada, Akira and Salama, Alan D and Sho, Masayuki and Najafian, Nader and Ito, Toshiro and Forman, John P and Kewalramani, Reshma and Sandner, Sigrid and Harada, Hiroshi and Clarkson, Michael R and Mandelbrot, Didier A and Sharpe, Arlene H and Oshima, Hideo and Yagita, Hideo and Chalasani, Geetha and Lakkis, Fadi G and Auchincloss, Hugh and Sayegh, Mohamed H}
}
@article {542561,
	title = {Dendritic cells giveth and taketh away.},
	journal = {Nat Immunol},
	volume = {6},
	number = {3},
	year = {2005},
	month = {2005 Mar},
	pages = {227-8},
	keywords = {Antigens, CD, Antigens, Differentiation, CTLA-4 Antigen, Dendritic Cells, Humans, Receptors, Immunologic, T-Lymphocytes},
	issn = {1529-2908},
	doi = {10.1038/ni0305-227},
	author = {Abbas, Abul K and Sharpe, Arlene H}
}
@article {542571,
	title = {Targeting of inducible costimulator (ICOS) expressed on alloreactive T cells down-regulates graft-versus-host disease (GVHD) and facilitates engraftment of allogeneic bone marrow (BM).},
	journal = {Blood},
	volume = {105},
	number = {8},
	year = {2005},
	month = {2005 Apr 15},
	pages = {3372-80},
	abstract = {Inducible costimulator (ICOS), a CD28/cytotoxic T lymphocyte antigen 4 (CTLA-4) family member, is expressed on activated T cells. ICOS ligand, a B7 family member, is constitutively expressed on B cells, macrophages, and dendritic cells and is up-regulated on antigen-presenting cells (APCs) and some nonlymphoid tissues by tumor necrosis factor alpha (TNFalpha) or lipopolysaccharide (LPS). Thus, ICOS: ICOS ligand (ICOSL) blockade could reduce alloreactive T cell-APC interactions responsible for graft-versus-host disease (GVHD) and bone marrow (BM) graft rejection. ICOS blockade, achieved with ICOS-/- mice or anti-ICOS monoclonal antibody (mAb) administration, resulted in significant inhibition of GVHD in multiple strain combinations whether mediated by CD4+ and/or CD8+ T cells, alloantigen-specific T-cell receptor (TCR) transgenic (Tg) T cells, or CD28-, T helper 1 (Th1)-, or Th2-deficient T cells. Anti-ICOS significantly delayed GVHD mortality even when mAb infusions were delayed until day 5 after transplantation. ICOS blockade reduced the number of alloantigen-specific effector cells but did not prevent their activation. Imaging of green fluorescent protein-positive (GFP+) effectors indicated that ICOS blockade inhibited expansion of GVHD-causing effector T cells in secondary lymphoid and GVHD target organs. Engraftment rates were significantly higher in ICOS-/- versus wild-type (WT) mice receiving allogeneic BM, and ICOS blockade significantly inhibited expansion of host antidonor alloantigen-specific BM graft-rejecting T cells. These data suggest that the ICOS pathway may be a beneficial therapeutic target for GVHD inhibition, GVHD therapy, and BM graft promotion.},
	keywords = {Animals, Antibodies, Monoclonal, Antigens, CD28, Antigens, Differentiation, T-Lymphocyte, Bone Marrow Transplantation, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, DNA-Binding Proteins, Down-Regulation, Graft Rejection, Graft Survival, Graft vs Host Disease, Inducible T-Cell Co-Stimulator Protein, Lymphoid Tissue, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Mutant Strains, Signal Transduction, STAT4 Transcription Factor, STAT6 Transcription Factor, Trans-Activators, Transplantation, Homologous},
	issn = {0006-4971},
	doi = {10.1182/blood-2004-10-3869},
	author = {Taylor, Patricia A and Panoskaltsis-Mortari, Angela and Freeman, Gordon J and Sharpe, Arlene H and Noelle, Randolph J and Rudensky, Alexander Y and Mak, Tak W and Serody, Jonathan S and Blazar, Bruce R}
}
@article {542536,
	title = {Analysis of the role of negative T cell costimulatory pathways in CD4 and CD8 T cell-mediated alloimmune responses in vivo.},
	journal = {J Immunol},
	volume = {174},
	number = {11},
	year = {2005},
	month = {2005 Jun 1},
	pages = {6648-56},
	abstract = {Negative costimulatory signals mediated via cell surface molecules such as CTLA-4 and programmed death 1 (PD-1) play a critical role in down-modulating immune responses and maintaining peripheral tolerance. However, their role in alloimmune responses remains unclear. This study examined the role of these inhibitory pathways in regulating CD28-dependent and CD28-independent CD4 and CD8 alloreactive T cells in vivo. CTLA-4 blockade accelerated graft rejection in C57BL/6 wild-type recipients and in a proportion of CD4(-/-) but not CD8(-/-) recipients of BALB/c hearts. The same treatment led to prompt rejection in CD28(-/-) and a smaller proportion of CD4(-/-)CD28(-/-) mice with no effect in CD8(-/-)CD28(-/-) recipients. These results indicate that the CTLA-4:B7 pathway provides a negative signal to alloreactive CD8(+) T cells, particularly in the presence of CD28 costimulation. In contrast, PD-1 blockade led to accelerated rejection of heart allografts only in CD28(-/-) and CD8(-/-)CD28(-/-) recipients. Interestingly, PD-1 ligand (PD-L1) blockade led to accelerated rejection in wild-type mice and in all recipients lacking CD28 costimulation. This effect was accompanied by expansion of IFN-gamma-producing alloreactive T cells and enhanced generation of effector T cells in rejecting allograft recipients. Thus, the PD-1:PD-L1 pathway down-regulates alloreactive CD4 T cells, particularly in the absence of CD28 costimulation. The differential effects of PD-1 vs PD-L1 blockade support the possible existence of a new receptor other than PD-1 for negative signaling through PD-L1. Furthermore, PD-1:PD-L1 pathway can regulate alloimmune responses independent of an intact CD28/CTLA-4:B7 pathway. Harnessing physiological mechanisms that regulate alloimmunity should lead to development of novel strategies to induce durable and reproducible transplantation tolerance.},
	keywords = {Animals, Antibodies, Blocking, Antigens, CD, Antigens, CD274, Antigens, CD28, Antigens, CD4, Antigens, CD8, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, CTLA-4 Antigen, Down-Regulation, Graft Rejection, Heart Transplantation, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Peptides, Programmed Cell Death 1 Ligand 2 Protein, Programmed Cell Death 1 Receptor, Signal Transduction},
	issn = {0022-1767},
	author = {Ito, Toshiro and Ueno, Takuya and Clarkson, Michael R and Yuan, Xueli and Jurewicz, Mollie M and Yagita, Hideo and Azuma, Miyuki and Sharpe, Arlene H and Auchincloss, Hugh and Sayegh, Mohamed H and Najafian, Nader}
}
@article {542556,
	title = {The B7 family revisited.},
	journal = {Annu Rev Immunol},
	volume = {23},
	year = {2005},
	month = {2005},
	pages = {515-48},
	abstract = {The discovery of new functions for the original B7 family members, together with the identification of additional B7 and CD28 family members, have revealed new ways in which the B7:CD28 family regulates T cell activation and tolerance. B7-1/B7-2:CD28 interactions not only promote initial T cell activation but also regulate self-tolerance by supporting CD4+CD25+ T regulatory cell homeostasis. CTLA-4 can exert its inhibitory effects in both B7-1/B7-2 dependent and independent fashions. B7-1 and B7-2 can signal bidirectionally by engaging CD28 and CTLA-4 on T cells and by delivering signals into B7-expressing cells. The five new B7 family members, ICOS ligand, PD-L1 (B7-H1), PD-L2 (B7-DC), B7-H3, and B7-H4 (B7x/B7-S1) are expressed on professional antigen-presenting cells as well as on cells within nonlymphoid organs, providing new means for regulating T cell activation and tolerance in peripheral tissues. The new CD28 families members, ICOS, PD-1, and BTLA, are inducibly expressed on T cells, and they have important roles in regulating previously activated T cells. PD-1 and BTLA also are expressed on B cells and may have broader immunoregulatory functions. The ICOS:ICOSL pathway appears to be particularly important for stimulating effector T cell responses and T cell-dependent B cell responses, but it also has an important role in regulating T cell tolerance. In addition, the PD-1:PD-L1/PD-L2 pathway plays a critical role in regulating T cell activation and tolerance. In this review, we revisit the roles of the B7:CD28 family members in regulating immune responses, and we discuss their therapeutic potential.},
	keywords = {Animals, Antigens, CD, Antigens, CD28, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, Antigens, Differentiation, T-Lymphocyte, Asthma, Autoimmunity, CTLA-4 Antigen, Humans, Hypersensitivity, Inducible T-Cell Co-Stimulator Ligand, Inducible T-Cell Co-Stimulator Protein, Infection, Membrane Glycoproteins, Mice, Proteins, Transplantation Immunology},
	issn = {0732-0582},
	doi = {10.1146/annurev.immunol.23.021704.115611},
	author = {Greenwald, Rebecca J and Freeman, Gordon J and Sharpe, Arlene H}
}
@article {542551,
	title = {The B7/CD28 costimulatory family in autoimmunity.},
	journal = {Immunol Rev},
	volume = {204},
	year = {2005},
	month = {2005 Apr},
	pages = {128-43},
	abstract = {Host defense is dependent on the appropriate induction of immune responses. A central concept in immunology is the ability of the immune system to differentiate foreign from self-antigens. The failure of the immune response to recognize foreign pathogens can result in infection and disease in the host. The inappropriate response of the immune system to self-antigens is equally problematic, leading to autoimmune disease. Central and peripheral tolerance mechanisms control self-reactive T-cell responses and protect peripheral tissues from autoimmune attack. This review examines the roles of B7/CD28 family members, which can augment or antagonize T-cell receptor signaling, in the regulation of central and peripheral T-cell tolerance. We also discuss how B7/CD28 pathways influence both T-cell-intrinsic and -extrinsic mechanisms of regulation.},
	keywords = {Animals, Antigens, CD28, Antigens, CD80, Autoimmunity, Dendritic Cells, Immune Tolerance, T-Lymphocytes},
	issn = {0105-2896},
	doi = {10.1111/j.0105-2896.2005.00242.x},
	author = {Keir, Mary E and Sharpe, Arlene H}
}
@article {542531,
	title = {ICOS contributes to T cell expansion in CTLA-4 deficient mice.},
	journal = {J Immunol},
	volume = {175},
	number = {1},
	year = {2005},
	month = {2005 Jul 1},
	pages = {182-8},
	abstract = {Both CD28 and ICOS are important costimulatory molecules that promote Ag-specific cellular and humoral immune reactions. Whereas CD28 is generally thought to be the most important molecule in the initiation of a T cell response, ICOS is considered to act during the effector phase. We have investigated the contribution of ICOS to T cell responses in the absence of CTLA-4-mediated inhibition. Mice lacking CTLA-4, which show spontaneous CD28-mediated CD4(+) T cell activation, expansion and differentiation, were treated with antagonistic alphaICOS antibodies. Blocking the interaction between ICOS and its ligand B7RP-1 significantly reduced this aberrant T cell activation and caused a reduction in T cell numbers. In vitro analysis of CD4(+) T cells from treated mice revealed that ICOS blockade significantly reduced Th1 differentiation, while Th2 differentiation was only moderately inhibited. Further in vitro stimulation experiments demonstrated that ICOS is able to induce proliferation of murine CD4(+) and CD8(+) T cells but only in the presence of IL-2. These results indicate that ICOS is not only important for T cell effector function but also contributes to the expansion phase of a T cell response in the presence of CD28 signaling.},
	keywords = {Animals, Antigens, CD, Antigens, CD28, Antigens, Differentiation, Antigens, Differentiation, T-Lymphocyte, Cell Differentiation, Cell Proliferation, CTLA-4 Antigen, In Vitro Techniques, Inducible T-Cell Co-Stimulator Protein, Interleukin-2, Mice, Mice, Inbred C57BL, Mice, Knockout, Signal Transduction, T-Lymphocyte Subsets, T-Lymphocytes},
	issn = {0022-1767},
	author = {van Berkel, Miranda E A T and Schrijver, Elise H R and Hofhuis, Frans M A and Sharpe, Arlene H and Coyle, Anthony J and Broeren, Chris P and Tesselaar, Kiki and Oosterwegel, Mari{\"e}tte A}
}
@article {542511,
	title = {The ICOS molecule plays a crucial role in the development of mucosal tolerance.},
	journal = {J Immunol},
	volume = {175},
	number = {11},
	year = {2005},
	month = {2005 Dec 1},
	pages = {7341-7},
	abstract = {The ICOS molecule stimulates production of the immunoregulatory cytokine IL-10, suggesting an important role for ICOS in controlling IL-10-producing regulatory T cells and peripheral T cell tolerance. In this study we investigate whether ICOS is required for development of oral, nasal, and high dose i.v. tolerance. Oral administration of encephalitogenic myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide to ICOS-deficient (ICOS-/-) mice did not inhibit experimental autoimmune encephalomyelitis (EAE), T cell proliferation, or IFN-gamma production, in striking contrast to wild-type mice. Similarly, intranasal administration of MOG(35-55) before EAE induction suppressed EAE and T cell responses in wild-type, but not in ICOS-/-, mice. In contrast, ICOS-/- mice were as susceptible as wild-type mice to high dose tolerance. These results indicate that ICOS plays an essential and specific role in mucosal tolerance and that distinct costimulatory pathways differentially regulate different forms of peripheral tolerance. Surprisingly, CD4+ cells from MOG-fed wild-type and ICOS-/- mice could transfer suppression to wild-type recipients, indicating that functional regulatory CD4+ cells can develop in the absence of ICOS. However, CD4+ T cells from MOG-fed wild-type mice could not transfer suppression to ICOS-/- recipients, suggesting that ICOS may have a key role in controlling the effector functions of regulatory T cells. These results suggest that stimulating ICOS may provide an effective therapeutic approach for promoting mucosal tolerance.},
	keywords = {Administration, Intranasal, Administration, Oral, Adoptive Transfer, Animals, Antigens, Differentiation, T-Lymphocyte, Cytokines, Dose-Response Relationship, Drug, Encephalomyelitis, Autoimmune, Experimental, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Glycoproteins, Immune Tolerance, Immunity, Mucosal, Inducible T-Cell Co-Stimulator Protein, Injections, Intravenous, Mice, Myelin-Oligodendrocyte Glycoprotein, Peptide Fragments, T-Lymphocytes, Regulatory},
	issn = {0022-1767},
	author = {Miyamoto, Katsuichi and Kingsley, Cherry I and Zhang, Xingmin and Jabs, Claudia and Izikson, Leonid and Sobel, Raymond A and Weiner, Howard L and Kuchroo, Vijay K and Sharpe, Arlene H}
}
@article {542546,
	title = {An important role of CD80/CD86-CTLA-4 signaling during photocarcinogenesis in mice.},
	journal = {J Immunol},
	volume = {174},
	number = {9},
	year = {2005},
	month = {2005 May 1},
	pages = {5298-305},
	abstract = {Although previous studies have shown that altered B7 costimulation plays a critical role in UV irradiation-induced regulation of immunity, the individual roles of the B7 receptors (CD28 and CTLA-4) or the B7 family members (CD80 and CD86) have not been explored. Thus, we investigated CTLA-4 signaling during photocarcinogenesis of chronically UV-B-exposed mice using an antagonistic anti-CTLA-4 Ab. Anti-CTLA-4-treated mice developed significantly fewer UV-induced tumors. Moreover, anti-CTLA-4 treatment induced long-lasting protective immunity because progressively growing UV tumors inoculated into anti-CTLA-4- and UV-treated mice that had not developed tumors were rejected. Next, we used mice deficient for CD80, CD86, or both in photocarcinogenesis studies to assess the relative contributions of these CTLA-4 ligands. Double-deficient mice showed significantly reduced UV-induced skin tumor development, whereas CD86(-/-) mice produced skin cancer earlier compared with CD80(-/-) and control mice. The growth of UV-induced tumors appears to be controlled by UV-induced suppressor T cells, because CD80(-/-)/CD86(-/-) mice had strongly reduced numbers of UV-induced CD4(+)CD25(+) suppressor T cells. In vitro, CTLA-4 blockade inhibited the suppressor activity of UV-induced CD4(+)CD25(+) T cells, suggesting that reduced photocarcinogenesis might be due to decreased numbers or function of suppressor T cells. Together, these data indicate that blocking CD80/86-CTLA-4 signaling induced immune protection against the development of UV-induced skin tumors. Furthermore, CD86-mediated costimulation appears to play a more critical role in the protection against photocarcinogenesis than CD80.},
	keywords = {Animals, Antibodies, Blocking, Antigens, CD, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, Bone Marrow Cells, Cell Line, Tumor, CTLA-4 Antigen, Dendritic Cells, Graft Rejection, Growth Inhibitors, Immunosuppressive Agents, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Knockout, Neoplasm Transplantation, Neoplasms, Radiation-Induced, Signal Transduction, Skin Neoplasms, T-Lymphocytes, Regulatory, Ultraviolet Rays},
	issn = {0022-1767},
	author = {Loser, Karin and Scherer, Andrea and Krummen, Mathias B W and Varga, Georg and Higuchi, Tetsuya and Schwarz, Thomas and Sharpe, Arlene H and Grabbe, Stephan and Bluestone, Jeffrey A and Beissert, Stefan}
}
@article {542521,
	title = {Modulation of surgical fibrosis by microbial zwitterionic polysaccharides.},
	journal = {Proc Natl Acad Sci U S A},
	volume = {102},
	number = {46},
	year = {2005},
	month = {2005 Nov 15},
	pages = {16753-8},
	abstract = {Bacterial carbohydrates have long been considered T cell-independent antigens that primarily induce humoral immune responses. Recently, it has been demonstrated that bacterial capsules that possess a zwitterionic charge motif can activate CD4(+) T cells after processing and presentation by antigen-presenting cells. Here we show that these zwitterionic polysaccharides can prevent T helper 1-mediated fibrosis by signaling for the release of IL-10 from CD4(+) T cells in vivo. IL-10 production by these T cells and their ability to prevent fibrosis is controlled by the inducible costimulator (ICOS)-ICOS ligand pathway. These data demonstrate that the interaction of the zwitterionic polysaccharides with T cells results in modulation of surgical fibrosis in vivo and suggest a previously undescribed approach to "harnessing" T cell function to prevent inflammatory tissue disorders in humans.},
	keywords = {Animals, Fibrosis, Flow Cytometry, Mice, Mice, Inbred C57BL, Polysaccharides, Postoperative Complications},
	issn = {0027-8424},
	doi = {10.1073/pnas.0505688102},
	author = {Ruiz-Perez, Begonia and Chung, Doo R and Sharpe, Arlene H and Yagita, Hideo and Kalka-Moll, Wiltrud M and Sayegh, Mohamed H and Kasper, Dennis L and Tzianabos, Arthur O}
}
@article {542526,
	title = {Rap1-GTP is a negative regulator of Th cell function and promotes the generation of CD4+CD103+ regulatory T cells in vivo.},
	journal = {J Immunol},
	volume = {175},
	number = {5},
	year = {2005},
	month = {2005 Sep 1},
	pages = {3133-9},
	abstract = {The small GTPase Rap1 is transiently activated during TCR ligation and regulates integrin-mediated adhesion. To understand the in vivo functions of Rap1 in regulating T cell immune responses, we generated transgenic (Tg) mice, which express the active GTP-bound mutant Rap1E63 in their T lymphocytes. Although Rap1E63-Tg T cells exhibited increased LFA-1-mediated adhesion, ERK1/2 activation and proliferation of Rap1E63-Tg CD4+ T cells were defective. Rap1E63-Tg T cells primed in vivo and restimulated with specific Ag in vitro, exhibited reduced proliferation and produced reduced levels of IL-2. Rap1E63-Tg mice had severely deficient T cell-dependent B cell responses, as determined by impaired Ig class switching. Rap1E63-Tg mice had an increased fraction of CD4+CD103+ regulatory T cells (Treg), which exhibited enhanced suppressive efficiency as compared with CD4+CD103+ Treg from normal littermate control mice. Depletion of CD103+ Treg significantly restored the impaired responses of Rap1E63-Tg CD4+ T cells. Thus Rap1-GTP is a negative regulator of Th cell responses and one mechanism responsible for this effect involves the increase of CD103+ Treg cell fraction. Our results show that Rap1-GTP promotes the generation of CD103+ Treg and may have significant implications in the development of strategies for in vitro generation of Treg for the purpose of novel immunotherapeutic approaches geared toward tolerance induction.},
	keywords = {Animals, Antigens, CD, CD4-Positive T-Lymphocytes, Cell Adhesion, Integrin alpha Chains, Interleukin-2, Lymphocyte Activation, Lymphocyte Function-Associated Antigen-1, Mice, Mice, Inbred C57BL, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, rap1 GTP-Binding Proteins, T-Lymphocytes, Helper-Inducer},
	issn = {0022-1767},
	author = {Li, Lequn and Greenwald, Rebecca J and Lafuente, Esther M and Tzachanis, Dimitrios and Berezovskaya, Alla and Freeman, Gordon J and Sharpe, Arlene H and Boussiotis, Vassiliki A}
}
@article {542506,
	title = {Programmed death-1 (PD-1):PD-ligand 1 interactions inhibit TCR-mediated positive selection of thymocytes.},
	journal = {J Immunol},
	volume = {175},
	number = {11},
	year = {2005},
	month = {2005 Dec 1},
	pages = {7372-9},
	abstract = {Positive selection during thymocyte development is driven by the affinity and avidity of the TCR for MHC-peptide complexes expressed in the thymus. In this study, we show that programmed death-1 (PD-1), a member of the B7/CD28 family of costimulatory receptors, inhibits TCR-mediated positive selection through PD-1 ligand 1 (PD-L1):PD-1 interactions. Transgenic mice that constitutively overexpress PD-1 on CD4+CD8+ thymocytes display defects in positive selection in vivo. Using an in vitro model system, we find that PD-1 is up-regulated following TCR engagement on CD4+CD8+ murine thymocytes. Coligation of TCR and PD-1 on CD4+CD8+ thymocytes with a novel PD-1 agonistic mAb inhibits the activation of ERK and up-regulation of bcl-2, both of which are downstream mediators essential for positive selection. Inhibitory signals through PD-1 can overcome the ability of positive costimulators, such as CD2 and CD28, to facilitate positive selection. Finally, defects in positive selection that result from PD-1 overexpression in thymocytes resolve upon elimination of PD-L1, but not PD-1 ligand 2, expression. PD-L1-deficient mice have increased numbers of CD4+CD8+ and CD4+ thymocytes, indicating that PD-L1 is involved in normal thymic selection. These data demonstrate that PD-1:PD-L1 interactions are critical to positive selection and play a role in shaping the T cell repertoire.},
	keywords = {Animals, Antigens, CD2, Antigens, CD274, Antigens, CD28, Antigens, CD4, Antigens, CD8, Antigens, CD80, Antigens, Differentiation, Cell Differentiation, Clonal Deletion, Extracellular Signal-Regulated MAP Kinases, Flow Cytometry, Immune Tolerance, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Peptides, Programmed Cell Death 1 Ligand 2 Protein, Programmed Cell Death 1 Receptor, Proto-Oncogene Proteins c-bcl-2, Receptors, Antigen, T-Cell, T-Lymphocytes, Thymus Gland},
	issn = {0022-1767},
	author = {Keir, Mary E and Latchman, Yvette E and Freeman, Gordon J and Sharpe, Arlene H}
}
@article {542616,
	title = {B7 expression on T cells down-regulates immune responses through CTLA-4 ligation via T-T interactions [corrections].},
	journal = {J Immunol},
	volume = {172},
	number = {1},
	year = {2004},
	month = {2004 Jan 1},
	pages = {34-9},
	abstract = {Although B7 on APCs has a well-recognized role in T cell costimulation, little is known about the functional significance of constitutive and activation-induced B7 expression that also occurs on T cells. To analyze the role of B7 on T cells, B7-1/B7-2-deficient mice (B7 double knockout) and mice overexpressing B7-2 exclusively on T cells (B7-2 transgenic) were used as T cell donors for allogeneic transplant recipients, and graft-vs-host disease (GVHD) was assessed. B7 double-knockout T cells resulted in significant GVHD acceleration compared with wild-type T cells. Conversely, B7-2 transgenic donor T cells mediated reduced GVHD mortality compared with wild-type T cells. Data indicated that B7 expression on T cells down-regulated alloresponses through CTLA-4 ligation. This study is the first to provide definitive in vivo data illustrating the importance of T cell-associated B7 as a negative regulator of immune responses in a clinically relevant murine model of GVHD. The up-regulation of B7 on T cells may be an important component of normal immune homeostasis.},
	keywords = {Animals, Antigen-Presenting Cells, Antigens, CD, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, Bone Marrow Transplantation, CD4-Positive T-Lymphocytes, Cell Communication, CTLA-4 Antigen, Down-Regulation, Graft vs Host Disease, Ligands, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Receptors, Interleukin-2, T-Lymphocyte Subsets, Up-Regulation},
	issn = {0022-1767},
	author = {Taylor, Patricia A and Lees, Christopher J and Fournier, Sylvie and Allison, James P and Sharpe, Arlene H and Blazar, Bruce R}
}
@article {542611,
	title = {B7-1/B7-2 costimulation regulates plaque antigen-specific T-cell responses and atherogenesis in low-density lipoprotein receptor-deficient mice.},
	journal = {Circulation},
	volume = {109},
	number = {16},
	year = {2004},
	month = {2004 Apr 27},
	pages = {2009-15},
	abstract = {BACKGROUND: Several lines of evidence indicate that T-cell responses influence the progression of atherosclerotic disease. Interferon-gamma (IFN-gamma)-producing T cells specific for lesional antigens, including oxidized LDLs and heat shock protein 60 (HSP60), may promote lesion development as well as plaque instability. B7-1 and B7-2 are closely related molecules expressed on antigen-presenting cells that provide costimulatory signals for T-cell activation. This study tested the hypothesis that the ability of T cells to influence atherosclerosis depends on B7-1/B7-2 costimulation.

METHODS AND RESULTS: B7-1/B7-2/LDL receptor (LDLR)-deficient mice and LDLR-deficient control mice were fed a 1.25\% cholesterol or control diet for 8 and 20 weeks. Total serum cholesterol levels and extent and phenotype of atherosclerosis were analyzed. Splenic and lymph node CD4+ T cells from the animals were cultured with mouse recombinant HSP60 or media and antigen-presenting cells and analyzed for IFN-gamma and interleukin-4 production. The absence of B7-1 and B7-2 significantly reduced early cholesterol diet-induced atherosclerotic lesion development in LDLR-deficient mice compared with B7-1/B7-2-expressing control mice. Furthermore, CD4+ T cells from the cholesterol-fed B7-deficient mice secreted a significantly lower amount of IFN-gamma in response to mouse HSP60 in vitro than did T cells from B7-expressing control mice.

CONCLUSIONS: The data show that B7-1 and B7-2 regulated the development of atherosclerotic lesions and the priming of lesional antigen-specific T cells. This study highlights the B7-CD28 pathway as a potentially important target for immunomodulation of atherosclerosis.},
	keywords = {Animals, Antigens, Antigens, CD, Antigens, CD80, Antigens, CD86, Arteriosclerosis, CD4-Positive T-Lymphocytes, Chaperonin 60, Cholesterol, Cytokines, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Knockout, Receptors, LDL},
	issn = {1524-4539},
	doi = {10.1161/01.CIR.0000127121.16815.F1},
	author = {Buono, Chiara and Pang, Hong and Uchida, Yasushi and Libby, Peter and Sharpe, Arlene H and Lichtman, Andrew H}
}
@article {542576,
	title = {4-1BB and OX40 act independently to facilitate robust CD8 and CD4 recall responses.},
	journal = {J Immunol},
	volume = {173},
	number = {10},
	year = {2004},
	month = {2004 Nov 15},
	pages = {5944-51},
	abstract = {Mice deficient in OX40 or 4-1BB costimulatory pathways show defects in T cell recall responses, with predominant effects on CD4 vs CD8 T cells, respectively. However, OX40L can also stimulate CD8 T cells and 4-1BBL can influence CD4 T cells, raising the possibility of redundancy between the two TNFR family costimulators. To test this possibility, we generated mice deficient in both 4-1BBL and OX40L. In an adoptive transfer model, CD4 T cells expressed 4-1BB and OX40 sequentially in response to immunization, with little or no overlap in the timing of their expression. Under the same conditions, CD8 T cells expressed 4-1BB, but no detectable OX40. Thus, in vivo expression of 4-1BB and OX40 can be temporally and spatially segregated. In the absence of OX40L, there were decreased CD4 T cells late in the primary response and no detectable secondary expansion of adoptively transferred CD4 T cells under conditions in which primary expansion was unaffected. The 4-1BBL had a minor effect on the primary response of CD4 T cells in this model, but showed larger effects on the secondary response, although 4-1BBL(-/-) mice show less impairment in CD4 secondary responses than OX40L(-/-) mice. The 4-1BBL(-/-) and double knockout mice were similarly impaired in the CD8 T cell response, whereas OX40L(-/-) and double knockout mice were similarly impaired in the CD4 T cell response to both protein Ag and influenza virus. Thus, 4-1BB and OX40 act independently and nonredundantly to facilitate robust CD4 and CD8 recall responses.},
	keywords = {4-1BB Ligand, Adoptive Transfer, Animals, Antigens, CD, Antigens, CD137, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Proliferation, Enterotoxins, Epitopes, T-Lymphocyte, Immunization, Secondary, Immunologic Memory, Influenza A virus, Ligands, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Receptors, Nerve Growth Factor, Receptors, OX40, Receptors, Tumor Necrosis Factor, Superantigens, Tumor Necrosis Factor-alpha, Tumor Necrosis Factors},
	issn = {0022-1767},
	author = {Dawicki, Wojciech and Bertram, Edward M and Sharpe, Arlene H and Watts, Tania H}
}
@article {542601,
	title = {An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells.},
	journal = {Immunity},
	volume = {20},
	number = {5},
	year = {2004},
	month = {2004 May},
	pages = {563-75},
	abstract = {Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) plays a critical role in downregulating T cell responses. A number of autoimmune diseases have shown genetic linkage to the CTLA-4 locus. We have cloned and expressed an alternatively spliced form of CTLA-4 that has genetic linkage with type I diabetes in the NOD mice. This splice variant of CTLA-4, named ligand-independent CTLA-4 (liCTLA-4), lacks exon2 including the MYPPPY motif essential for binding to the costimulatory ligands B7-1 and B7-2. Here we show that liCTLA-4 is expressed as a protein in primary T cells and strongly inhibits T cell responses by binding and dephosphorylating the TcRzeta chain. Expression of liCTLA-4, but not full-length CTLA-4 (flCTLA-4), was higher in memory/regulatory T cells from diabetes-resistant NOD congenic mice compared to susceptible NOD mice. These data suggest that increased expression and negative signaling delivered by the liCTLA-4 may regulate development of T cell-mediated autoimmune diseases.},
	keywords = {Amino Acid Sequence, Animals, Antigens, CD, Antigens, CD80, Antigens, Differentiation, Autoimmune Diseases, Blotting, Western, Cloning, Molecular, CTLA-4 Antigen, Female, Flow Cytometry, Humans, Membrane Proteins, Mice, Mice, Inbred NOD, Molecular Sequence Data, Receptors, Antigen, T-Cell, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Signal Transduction, T-Lymphocytes},
	issn = {1074-7613},
	author = {Vijayakrishnan, Lalitha and Slavik, Jacqueline M and Ill{\'e}s, Zsolt and Greenwald, Rebecca J and Rainbow, Dan and Greve, Bernhard and Peterson, Laurence B and Hafler, David A and Freeman, Gordon J and Sharpe, Arlene H and Wicker, Linda S and Kuchroo, Vijay K}
}
@article {542606,
	title = {The cell surface receptor SLAM controls T cell and macrophage functions.},
	journal = {J Exp Med},
	volume = {199},
	number = {9},
	year = {2004},
	month = {2004 May 3},
	pages = {1255-64},
	abstract = {Signaling lymphocyte activation molecule (SLAM), a glycoprotein expressed on activated lymphocytes and antigen-presenting cells, has been shown to be a coregulator of antigen-driven T cell responses and is one of the two receptors for measles virus. Here we show that T cell receptor-induced interleukin (IL)-4 secretion by SLAM(-/-) CD4(+) cells is down-regulated, whereas interferon gamma production by CD4(+) T cells is only slightly up-regulated. Although SLAM controls production of IL-12, tumor necrosis factor, and nitric oxide in response to lipopolysaccharide (LPS) by macrophages, SLAM does not regulate phagocytosis and responses to peptidoglycan or CpG. Thus, SLAM acts as a coreceptor that regulates signals transduced by the major LPS receptor Toll-like receptor 4 on the surface of mouse macrophages. A defective macrophage function resulted in an inability of SLAM(-/-) C57Bl/6 mice to remove the parasite Leishmania major. We conclude that the coreceptor SLAM plays a central role at the interface of acquired and innate immune responses.},
	keywords = {Animals, Antigens, CD, Base Sequence, CD4-Positive T-Lymphocytes, DNA Primers, Glycoproteins, Immunoglobulins, Leishmania major, Leishmaniasis, Cutaneous, Lipopolysaccharides, Macrophages, Peritoneal, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Mutant Strains, Receptors, Antigen, T-Cell, Receptors, Antigen, T-Cell, alpha-beta, Receptors, Cell Surface, Recombinant Proteins, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes},
	issn = {0022-1007},
	doi = {10.1084/jem.20031835},
	author = {Wang, Ninghai and Satoskar, Abhay and Faubion, William and Howie, Duncan and Okamoto, Susumu and Feske, Stefan and Gullo, Charles and Clarke, Kareem and Sosa, Miriam Rodriguez and Sharpe, Arlene H and Terhorst, Cox}
}
@article {542581,
	title = {Deletion of a conserved Il4 silencer impairs T helper type 1-mediated immunity.},
	journal = {Nat Immunol},
	volume = {5},
	number = {12},
	year = {2004},
	month = {2004 Dec},
	pages = {1251-9},
	abstract = {Helper T cell differentiation involves silencing as well as activation of gene expression. We have identified a conserved silencer of the gene encoding interleukin 4 (Il4) marked by DNase I hypersensitivity (HS IV) and permissive chromatin structure in all helper T cells. Deletion of HS IV increased Il4 and Il13 transcription by naive T cells and led to T helper type 2 skewing in vitro. HS IV controlled Il4 silencing during T helper type 1 differentiation, as HS IV-deficient T helper type 1 cells that expressed interferon-gamma also produced abundant interleukin 4 in vitro and in vivo. Despite mounting a vigorous interferon-gamma response, HS IV-deficient mice were more susceptible to Leishmania major infection than were wild-type littermate control mice, showing a critical function for Il4 silencing in T helper type 1-mediated immunity.},
	keywords = {Animals, Cell Differentiation, Cells, Cultured, Chromatin, Conserved Sequence, Cytokines, Deoxyribonuclease I, Gene Expression Regulation, Gene Silencing, Genetic Predisposition to Disease, Interleukin-4, Leishmania major, Leishmaniasis, Cutaneous, Mice, Mice, Knockout, Regulatory Sequences, Nucleic Acid, Sequence Deletion, Th1 Cells, Th2 Cells},
	issn = {1529-2908},
	doi = {10.1038/ni1135},
	author = {Ansel, K Mark and Greenwald, Rebecca J and Agarwal, Suneet and Bassing, Craig H and Monticelli, Silvia and Interlandi, Jeneen and Djuretic, Ivana M and Lee, Dong U and Sharpe, Arlene H and Alt, Frederick W and Rao, Anjana}
}
@article {542596,
	title = {Induction of B7-1 in podocytes is associated with nephrotic syndrome.},
	journal = {J Clin Invest},
	volume = {113},
	number = {10},
	year = {2004},
	month = {2004 May},
	pages = {1390-7},
	abstract = {Kidney podocytes and their slit diaphragms form the final barrier to urinary protein loss. This explains why podocyte injury is typically associated with nephrotic syndrome. The present study uncovered an unanticipated novel role for costimulatory molecule B7-1 in podocytes as an inducible modifier of glomerular permselectivity. B7-1 in podocytes was found in genetic, drug-induced, immune-mediated, and bacterial toxin-induced experimental kidney diseases with nephrotic syndrome. The clinical significance of our results is underscored by the observation that podocyte expression of B7-1 correlated with the severity of human lupus nephritis. In vivo, exposure to low-dose LPS rapidly upregulates B7-1 in podocytes of WT and SCID mice, leading to nephrotic-range proteinuria. Mice lacking B7-1 are protected from LPS-induced nephrotic syndrome, suggesting a link between podocyte B7-1 expression and proteinuria. LPS signaling through toll-like receptor-4 reorganized the podocyte actin cytoskeleton in vitro, and activation of B7-1 in cultured podocytes led to reorganization of vital slit diaphragm proteins. In summary, upregulation of B7-1 in podocytes may contribute to the pathogenesis of proteinuria by disrupting the glomerular filter and provides a novel molecular target to tackle proteinuric kidney diseases. Our findings suggest a novel function for B7-1 in danger signaling by nonimmune cells.},
	keywords = {Actins, Animals, Antigens, CD80, Base Sequence, DNA, Humans, In Vitro Techniques, Integrin alpha3, Kidney, Lipopolysaccharides, Lupus Nephritis, Membrane Glycoproteins, Membrane Proteins, Mice, Mice, Knockout, Mice, SCID, Nephrotic Syndrome, Proteins, Receptors, Cell Surface, Signal Transduction, Toll-Like Receptor 4, Toll-Like Receptors},
	issn = {0021-9738},
	doi = {10.1172/JCI20402},
	author = {Reiser, Jochen and von Gersdorff, Gero and Loos, Martin and Oh, Jun and Asanuma, Katsuhiko and Giardino, Laura and Rastaldi, Maria Pia and Calvaresi, Novella and Watanabe, Haruko and Schwarz, Karin and Faul, Christian and Kretzler, Matthias and Davidson, Anne and Sugimoto, Hikaru and Kalluri, Raghu and Sharpe, Arlene H and Kreidberg, Jordan A and Mundel, Peter}
}
@article {542586,
	title = {Mechanism of action of donor-specific transfusion in inducing tolerance: role of donor MHC molecules, donor co-stimulatory molecules, and indirect antigen presentation.},
	journal = {J Am Soc Nephrol},
	volume = {15},
	number = {9},
	year = {2004},
	month = {2004 Sep},
	pages = {2423-8},
	abstract = {Donor-specific transfusion (DST) can synergize with T cell co-stimulatory blockade in inducing tolerance in several transplant models, but the mechanism of action of DST is poorly characterized. This study used genetically altered mice in an established model of cardiac transplantation to study the role of MHC and co-stimulatory molecule expression on DST cells in mediating the immunomodulatory effects of DST. In addition, to examine the role of indirect antigen presentation in the effect of DST, experiments used recipient mice that do not express MHC class II molecules on peripheral antigen-presenting cells, but do have functional CD4(+) T cells (II(-)4(+)). As previously reported, treatment with DST from wild-type donors in combination with CD154 blockade induced tolerance in wild-type recipients of cardiac allografts. Tolerance in this model is also induced despite the absence of MHC class I and II, CD40, or B7 molecules on transfused cells. In contrast, eliminating the indirect pathway using II(-)4(+) recipients blocked the induction of long-term cardiac allograft survival by DST. These results indicate that the indirect antigen recognition pathway mediates the immunomodulatory effect of DST in inducing transplantation tolerance in vivo.},
	keywords = {Animals, Antibodies, Monoclonal, Antigen Presentation, Biological Therapy, CD40 Ligand, Genes, MHC Class II, Graft Survival, Heart Transplantation, Mice, Mice, Inbred C57BL, Spleen, Tissue Donors, Transplantation Immunology, Transplantation Tolerance},
	issn = {1046-6673},
	doi = {10.1097/01.ASN.0000137883.20961.2D},
	author = {Kishimoto, Koji and Yuan, Xueli and Auchincloss, Hugh and Sharpe, Arlene H and Mandelbrot, Didier A and Sayegh, Mohamed H}
}
@article {542591,
	title = {PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells.},
	journal = {Proc Natl Acad Sci U S A},
	volume = {101},
	number = {29},
	year = {2004},
	month = {2004 Jul 20},
	pages = {10691-6},
	abstract = {Both positive and negative regulatory roles have been suggested for the B7 family member PD-L1(B7-H1). PD-L1 is expressed on antigen-presenting cells (APCs), activated T cells, and a variety of tissues, but the functional significance of PD-L1 on each cell type is not yet clear. To dissect the functions of PD-L1 in vivo, we generated PD-L1-deficient (PD-L1(-/-)) mice. CD4(+) and CD8(+) T cell responses were markedly enhanced in PD-L1(-/-) mice compared with wild-type mice in vitro and in vivo. PD-L1(-/-) dendritic cells stimulated greater wild-type CD4(+) T cell responses than wild-type dendritic cells, and PD-L1(-/-) CD4(+) T cells produced more cytokines than wild-type CD4(+) T cells in vitro, demonstrating an inhibitory role for PD-L1 on APCs and T cells. In vivo CD8(+) T cell responses also were significantly enhanced, indicating that PD-L1 has a role in limiting the expansion or survival of CD8(+) T cells. Studies using the myelin oligodendrocyte model of experimental autoimmune encephalomyelitis showed that PD-L1 on T cells and in host tissues limits responses of self-reactive CD4(+) T cells in vivo. PD-L1 deficiency converted the 129S4/SvJae strain from a resistant to experimental autoimmune encephalomyelitis-susceptible strain. Transfer of encephalitogenic T cells from wild-type mice into PD-L1(-/-) recipients led to exacerbated disease. Disease was even more severe in PD-L1(-/-) recipients of PD-L1(-/-) T cells. These results demonstrate that PD-L1 on T cells, APCs, and host tissue inhibits na{\"\i}ve and effector T cell responses and plays a critical role in T cell tolerance.},
	keywords = {Adoptive Transfer, Animals, Antigen-Presenting Cells, Antigens, CD274, Antigens, CD80, Blood Proteins, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Encephalomyelitis, Autoimmune, Experimental, Immune Tolerance, Immunization, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Knockout, Peptides, Phenotype},
	issn = {0027-8424},
	doi = {10.1073/pnas.0307252101},
	author = {Latchman, Yvette E and Liang, Spencer C and Wu, Yin and Chernova, Tatyana and Sobel, Raymond A and Klemm, Martina and Kuchroo, Vijay K and Freeman, Gordon J and Sharpe, Arlene H}
}
@article {542661,
	title = {The role of OX40 ligand interactions in the development of the Th2 response to the gastrointestinal nematode parasite Heligmosomoides polygyrus.},
	journal = {J Immunol},
	volume = {170},
	number = {1},
	year = {2003},
	month = {2003 Jan 1},
	pages = {384-93},
	abstract = {In these studies, we examined the effects of OX40 ligand (OX40L) deficiency on the development of Th2 cells during the Th2 immune response to the intestinal nematode parasite Heligmosomoides polygyrus. Elevations in IL-4 production and total and Ag-specific serum IgE levels were partially inhibited during both the primary and memory immune responses to H. polygyrus in OX40L(-/-) mice. The host-protective memory response was compromised in OX40L(-/-) mice, as decreased worm expulsion and increased egg production were observed compared with H. polygyrus-inoculated OX40L(+/+) mice. To further examine the nature of the IL-4 defect during priming, adoptively transferred DO11.10 T cells were analyzed in the context of the H. polygyrus response. Although Ag-specific T cell IL-4 production was reduced in the OX40L(-/-) mice following immunization with OVA peptide plus H. polygyrus, Ag-specific T cell expansion, cell cycle progression, CXCR5 expression, and migration were comparable between OX40L(+/+) and OX40L(-/-) mice inoculated with OVA and H. polygyrus. These studies suggest an important role for OX40/OX40L interactions in specifically promoting IL-4 production, as well as associated IgE elevations, in Th2 responses to H. polygyrus. However, OX40L interactions were not required for serum IgG1 elevations, increases in germinal center formation, and Ag-specific Th2 cell expansion and migration to the B cell zone.},
	keywords = {Amino Acid Sequence, Animals, Antigens, CD27, Antigens, Helminth, B-Lymphocyte Subsets, Cell Cycle, Cell Movement, Chemokines, CXC, Epitopes, T-Lymphocyte, Germinal Center, Host-Parasite Interactions, Immunity, Innate, Immunization, Secondary, Immunoglobulin E, Immunoglobulin G, Injections, Subcutaneous, Interleukin-4, Intestinal Diseases, Parasitic, Ligands, Lymph Nodes, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Transgenic, Molecular Sequence Data, Neck, Nematospiroides dubius, Ovalbumin, Peptide Fragments, Receptors, Chemokine, Receptors, CXCR5, Receptors, Cytokine, Receptors, OX40, Receptors, Tumor Necrosis Factor, Strongylida Infections, Th2 Cells, Tumor Necrosis Factors, Up-Regulation},
	issn = {0022-1767},
	author = {Ekkens, Melinda J and Liu, Zhugong and Liu, Qian and Whitmire, Jeannette and Xiao, Shiyun and Foster, Anthony and Pesce, John and VanNoy, Jansie and Sharpe, Arlene H and Urban, Joseph F and Gause, William C}
}
@article {542621,
	title = {Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis.},
	journal = {Eur J Immunol},
	volume = {33},
	number = {11},
	year = {2003},
	month = {2003 Nov},
	pages = {3117-26},
	abstract = {Interactions between CD8+ T cells and endothelial cells are important in both protective and pathologic immune responses. Endothelial cells regulate the recruitment of CD8+ T cells into tissues, and the activation of CD8+ T cells by antigen presentation and costimulatory signals. PD-L1 and PD-L2 are recently described B7-family molecules which bind to PD-1 on activated lymphocytes and down-regulate T cell activation. We found that PD-L1 is expressed on interferon-gamma stimulated cultured human and mouse endothelial cells, while PD-L2 was found on stimulated human but not mouse endothelial cells. Expression was further up-regulated by TNF-alpha. Antibody blockade of endothelial cell PD-L1 and PD-L2 enhanced endothelial cell costimulation of PHA-activated human CD8+ T cells. Antibody blockade of mouse endothelial cell PD-L1 enhanced both IFN-gamma secretion and cytolytic activity of CD8+ T cells in response to endothelial cell antigen presentation. These results show that IFN-gamma activated endothelial cells can inhibit T cell activation via expression of the immunoinhibitory PD-L1 and PD-L2 molecules. Endothelial expression of PD-ligands would allow activation and extravasation of T cells without excessive vessel damage. Our findings highlight a potentially important pathway by which endothelial cells down-regulate CD8+ T cell-mediated immune responses.},
	keywords = {Animals, Antigen-Presenting Cells, Antigens, CD, Antigens, CD274, Antigens, CD80, Blood Proteins, CD8-Positive T-Lymphocytes, Endothelium, Vascular, Humans, Intercellular Signaling Peptides and Proteins, Membrane Glycoproteins, Mice, Peptides, Programmed Cell Death 1 Ligand 2 Protein},
	issn = {0014-2980},
	doi = {10.1002/eji.200324270},
	author = {Rodig, Nancy and Ryan, Timothy and Allen, Jessica A and Pang, Hong and Grabie, Nir and Chernova, Tatyana and Greenfield, Edward A and Liang, Spencer C and Sharpe, Arlene H and Lichtman, Andrew H and Freeman, Gordon J}
}
@article {542646,
	title = {The inhibitory function of B7 costimulators in T cell responses to foreign and self-antigens.},
	journal = {Nat Immunol},
	volume = {4},
	number = {7},
	year = {2003},
	month = {2003 Jul},
	pages = {664-9},
	abstract = {When antigen-presenting cells (APCs) encounter inflammatory stimuli, they up-regulate their expression of B7. A small amount of B7 is also constitutively expressed on resting APCs, but its function is unclear. Here we show that initiation of T cell responses requires the expression of B7 on immunizing APCs, but the responses are much greater in the absence of basal B7 expression. Transfer of antigen-specific CD4+CD25+ cells reverses the increased responsiveness, and tolerance to a self-protein is broken by immunization in the absence of basal B7, thereby inducing autoimmunity. Similar loss of self-tolerance is seen on depletion of CD25+ cells. Thus, constitutively expressed B7 costimulators function to suppress T cell activation and maintain self-tolerance, principally by sustaining a population of regulatory T cells.},
	keywords = {Animals, Antigens, CD, Antigens, CD80, Antigens, Differentiation, Autoantigens, Autoimmunity, CTLA-4 Antigen, Female, Immunoconjugates, Male, Mice, Mice, Inbred BALB C, Ovalbumin, Receptors, Interleukin-2, T-Lymphocytes, T-Lymphocytes, Helper-Inducer},
	issn = {1529-2908},
	doi = {10.1038/ni939},
	author = {Lohr, Jens and Knoechel, Birgit and Jiang, Shuwei and Sharpe, Arlene H and Abbas, Abul K}
}
@article {542656,
	title = {Ligation of OX40 (CD134) regulates graft-versus-host disease (GVHD) and graft rejection in allogeneic bone marrow transplant recipients.},
	journal = {Blood},
	volume = {101},
	number = {9},
	year = {2003},
	month = {2003 May 1},
	pages = {3741-8},
	abstract = {OX40 (CD134) is expressed on activated T cells; its ligand, OX40 ligand (OX40L) is expressed on dendritic cells, B cells, and activated endothelial cells. To determine how OX40-OX40L interaction affects graft-versus-host disease (GVHD), we used antagonistic anti-OX40L monoclonal antibody (mAb) or OX40(-/-) donor or OX40L(-/-) recipient mice. Similar degrees of GVHD reduction were observed with each approach. Despite the fact that OX40 is up-regulated on both CD4(+) and CD8(+) T cells isolated during GVHD, the major effects of OX40 ligation were on CD4(+) and not CD8(+) T-cell-mediated alloresponses as assessed in both GVHD and engraftment model systems. GVHD inhibition by blockade of the OX40/OX40L pathway did not require CD28 signaling. Some studies have indicated OX40 is essential for inducing T-helper type 2 (Th2) responses. However, in vivo blockade of OX40-OX40L interactions reduced GVHD mortality induced by either signal transducer and activator of transcription-6(-/-) (Stat-6(-/-)) (Th2-defective) or Stat-4(-/-) (Th1-defective) major histocompatibility complex (MHC)-disparate splenocytes, indicating that the GVHD-ameliorating effects did not require Stat-4 or Stat-6 signaling. Although OX40L has been reported to be expressed on activated T cells, no effects on GVHD were observed when OX40L(-/-) versus OX40L(+/+) T cells were infused in different models. These data provide insights as to the mechanisms responsible for OX40/OX40L regulation of GVHD.},
	keywords = {Animals, Antibodies, Monoclonal, Antibody Specificity, Antigens, CD27, Antigens, CD28, Bone Marrow Transplantation, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Crosses, Genetic, Dendritic Cells, DNA-Binding Proteins, Graft Rejection, Graft vs Host Disease, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, SCID, Radiation Chimera, Receptors, OX40, Receptors, Tumor Necrosis Factor, Signal Transduction, Specific Pathogen-Free Organisms, STAT4 Transcription Factor, STAT6 Transcription Factor, Th1 Cells, Th2 Cells, Trans-Activators, Transplantation, Homologous, Tumor Necrosis Factors},
	issn = {0006-4971},
	doi = {10.1182/blood-2002-10-3048},
	author = {Blazar, Bruce R and Sharpe, Arlene H and Chen, Andy I and Panoskaltsis-Mortari, Angela and Lees, Christopher and Akiba, Hisaya and Yagita, Hideo and Killeen, Nigel and Taylor, Patricia A}
}
@article {542636,
	title = {Recovery from EAE is associated with decreased survival of encephalitogenic T cells in the CNS of B7-1/B7-2-deficient mice.},
	journal = {Eur J Immunol},
	volume = {33},
	number = {7},
	year = {2003},
	month = {2003 Jul},
	pages = {2022-2032},
	abstract = {Adoptive transfer experiments using C57BL/6 mice lacking B7-1 and B7-2 as recipients of wt (wt) encephalitogenic T cells demonstrate a key role for B7 costimulation during the effector phase of experimental autoimmune encephalomyelitis (EAE). Following transfer of encephalitogenic T cells, B7-1/B7-2-deficient (-/-) recipients develop a transient and mild disease as compared to wt recipients. To understand the mechanism by which B7-1/B7-2 may influence the effector phase of EAE, we analyzed T cells, pro-inflammatory cytokines and chemokines within the CNS of wt and B7-1/B7-2-/- recipients at different times after adoptive transfer of activated myelin specific T cells. There was a marked decline in T cells and inflammatory mediators in the CNS of B7-1/B7-2-/- recipients by day 30 post transfer. B7-1/B7-2-/- mice developed more TUNEL+ apoptotic cells in the parenchyma and greater ratios of TUNEL+ cells/parenchymal foci than wt mice resulting in virtual disappearance of parenchymal foci. Therefore, without B7-1 and B7-2 costimulation in the target organ, there is increased T cell apoptosis and attenuation of inflammation. These results indicate that B7-1 and B7-2 provide critical costimulatory signals for sustaining survival of pathogenic T cells within the central nervous system parenchyma during the effector phase of EAE and suggest novel treatment approaches in the effector phase of autoimmune diseases.},
	keywords = {Animals, Antigens, CD, Antigens, CD80, Antigens, CD86, Apoptosis, Cell Survival, Central Nervous System, Encephalomyelitis, Autoimmune, Experimental, Membrane Glycoproteins, Mice, T-Lymphocytes},
	issn = {0014-2980},
	doi = {10.1002/eji.200323180},
	author = {Chang, Tammy T and Sobel, Raymond A and Wei, Tao and Ransohoff, Richard M and Kuchroo, Vijay K and Sharpe, Arlene H}
}
@article {542626,
	title = {Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses.},
	journal = {Eur J Immunol},
	volume = {33},
	number = {10},
	year = {2003},
	month = {2003 Oct},
	pages = {2706-16},
	abstract = {Newer members of the B7-CD28 superfamily include the receptor PD-1 and its two ligands, PD-L1 and PD-L2. Here, we characterize the expression of PD-1, PD-L1, and PD-L2 in tissues of naive miceand in target organs from two models of autoimmunity, the pancreas from non-obese diabetic (NOD) mice and brain from mice with experimental autoimmune encephalomyelitis (EAE). In naive mice, proteiexpression of PD-1, PD-L1, and PD-L2 was detected in the thymus, while PD-1 and PD-L1 were detected in the spleen. PD-L1, but not PD-L2, was also detected at low levels on cardiac endothelium, pancreatic islets, and syncyciotrophoblasts in the placenta. In pre-diabetic NOD mice, PD-1 and PD-L1 were expressed on infiltrating cells in the pancreatic islets. Furthermore, PD-L1 was markedly up-regulated on islet cells. In brains from mice with EAE, PD-1, PD-L1, and PD-L2 were expressed on infiltrating inflammatory cells, and PD-L1 was up-regulated on endothelium within EAE brain. The distinct expression patterns of PD-L1 and PD-L2 led us to compare their transcriptional regulation in STAT4(-/-), STAT6(-/-), or NF-kappaB p50(-/-)p65(+/-) dendritic cells (DC).PD-L2, but not PD-L1, expression was dramatically reduced in p50(-/-)p65(+/-) DC. Thus, PD-L1 and PD-L2 exhibit distinct expression patterns and are differentially regulated on the transcriptional level.},
	keywords = {Animals, Antigens, CD274, Antigens, CD80, Antigens, Surface, Apoptosis Regulatory Proteins, Autoimmune Diseases, Blood Proteins, CHO Cells, Cricetinae, Encephalomyelitis, Autoimmune, Experimental, Germinal Center, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred NOD, NF-kappa B, Peptides, Programmed Cell Death 1 Ligand 2 Protein, Programmed Cell Death 1 Receptor, Spleen, STAT6 Transcription Factor, Thymus Gland, Trans-Activators, Transfection, Up-Regulation},
	issn = {0014-2980},
	doi = {10.1002/eji.200324228},
	author = {Liang, Spencer C and Latchman, Yvette E and Buhlmann, Janet E and Tomczak, Michal F and Horwitz, Bruce H and Freeman, Gordon J and Sharpe, Arlene H}
}
@article {542651,
	title = {A role for the B7-1/B7-2:CD28/CTLA-4 pathway during negative selection.},
	journal = {J Immunol},
	volume = {170},
	number = {11},
	year = {2003},
	month = {2003 Jun 1},
	pages = {5421-8},
	abstract = {Although costimulation plays an important role in activating naive T cells, its role in negative selection is controversial. By following thymocyte deletion induced by endogenous superantigens in mice lacking B7-1 and/or B7-2, we have identified a role for both B7-1 and B7-2 in negative selection. Studies using CD28-deficient and CD28/CTLA-4-double-deficient mice have revealed that either CD28 or another as yet undefined coreceptor can mediate these B7-dependent signals that promote negative selection. Finally, CTLA-4 delivers signals that inhibit selection, suggesting that CTLA-4 and CD28 have opposing functions in thymic development. Combined, the data demonstrate that B7-1/B7-2-dependent signals help shape the T cell repertoire.},
	keywords = {Animals, Antigens, CD, Antigens, CD28, Antigens, CD40, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, Cell Differentiation, Clonal Deletion, CTLA-4 Antigen, Down-Regulation, Enterotoxins, Lymphocyte Depletion, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Knockout, Signal Transduction, Staphylococcus aureus, Superantigens, T-Lymphocyte Subsets},
	issn = {0022-1767},
	author = {Buhlmann, Janet E and Elkin, Sheryl Krevsky and Sharpe, Arlene H}
}
@article {542641,
	title = {The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity.},
	journal = {J Clin Invest},
	volume = {112},
	number = {2},
	year = {2003},
	month = {2003 Jul},
	pages = {234-43},
	abstract = {Inducible costimulatory molecule (ICOS) plays a pivotal role in T cell activation and Th1/Th2 differentiation. ICOS blockade has disparate effects on immune responses depending on the timing of blockade. Its role in transplantation immunity, however, remains incompletely defined. We used a vascularized mouse cardiac allograft model to explore the role of ICOS signaling at different time points after transplantation, targeting immune initiation (early blockade) or the immune effector phase (delayed blockade). In major histocompatibility-mismatched recipients, ICOS blockade prolonged allograft survival using both protocols but did so more effectively in the delayed-treatment group. By contrast, in minor histocompatibility-mismatched recipients, early blockade accelerated rejection and delayed blockade prolonged graft survival. Alloreactive CD4+ T cell expansion and alloantibody production were suppressed in both treatment groups, whereas only delayed blockade resulted in suppression of effector CD8+ T cell generation. After delayed ICOS blockade, there was a diminished frequency of allospecific IL-10-producing cells and an increased frequency of both IFN-gamma- and IL-4-producing cells. The beneficial effects of ICOS blockade in regulating allograft rejection were seen in the absence of CD28 costimulation but required CD8+ cells, cytotoxic T lymphocyte antigen-4, and an intact signal transducer and activator of transcription-6 pathway. These data define the complex functions of the ICOS-B7h pathway in regulating alloimmune responses in vivo.},
	keywords = {Animals, Antigens, CD28, Apoptosis, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cytokines, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Graft Rejection, Inducible T-Cell Co-Stimulator Ligand, Interferon-gamma, Interleukin-4, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Proteins, Receptors, Antigen, T-Cell, Signal Transduction, Spleen, STAT6 Transcription Factor, T-Lymphocytes, Time Factors, Trans-Activators},
	issn = {0021-9738},
	doi = {10.1172/JCI17008},
	author = {Harada, Hiroshi and Salama, Alan D and Sho, Masayuki and Izawa, Atsushi and Sandner, Sigrid E and Ito, Toshiro and Akiba, Hisaya and Yagita, Hideo and Sharpe, Arlene H and Freeman, Gordon J and Sayegh, Mohamed H}
}
@article {542631,
	title = {The threshold pattern of calcineurin-dependent gene expression is altered by loss of the endogenous inhibitor calcipressin.},
	journal = {Nat Immunol},
	volume = {4},
	number = {9},
	year = {2003},
	month = {2003 Sep},
	pages = {874-81},
	abstract = {Calcineurin links calcium signaling to transcriptional responses in the immune, nervous and cardiovascular systems. To determine the function of the calcipressins, a family of putative calcineurin inhibitors, we assessed the calcineurin-dependent process of T cell activation in mice engineered to lack the gene encoding calcipressin 1 (Csp1). Csp1 regulated calcineurin in vivo, and genes triggered in an immune response had unique transactivation thresholds for T cell receptor stimulation. In the absence of Csp1, the apparent transactivation thresholds for all these genes were shifted because of enhanced calcineurin activity. This unbridled calcineurin activity drove Fas ligand expression, which normally requires high T cell receptor stimulation and results in the premature death of T helper type 1 cells. Thus, calcipressins modulate the pattern of calcineurin-dependent transcription, and may influence calcineurin activity beyond calcium to integrate a broad array of signals into the cellular response.},
	keywords = {Animals, Apoptosis, Calcineurin, Calcineurin Inhibitors, Calcium, CD4-Positive T-Lymphocytes, DNA-Binding Proteins, Fas Ligand Protein, Gene Expression Regulation, Interferon-gamma, Intracellular Signaling Peptides and Proteins, Membrane Glycoproteins, Mice, Mice, Knockout, Muscle Proteins, NFATC Transcription Factors, Nuclear Proteins, Phosphorylation, Proteins, Th1 Cells, Transcription Factors, Transcriptional Activation},
	issn = {1529-2908},
	doi = {10.1038/ni966},
	author = {Ryeom, Sandra and Greenwald, Rebecca J and Sharpe, Arlene H and McKeon, Frank}
}
@article {542711,
	title = {Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity.},
	journal = {Nat Med},
	volume = {8},
	number = {9},
	year = {2002},
	month = {2002 Sep},
	pages = {1024-32},
	abstract = {Asthma is caused by T-helper cell 2 (Th2)-driven immune responses, but the immunological mechanisms that protect against asthma development are poorly understood. T-cell tolerance, induced by respiratory exposure to allergen, can inhibit the development of airway hyperreactivity (AHR), a cardinal feature of asthma, and we show here that regulatory T (T(R)) cells can mediate this protective effect. Mature pulmonary dendritic cells in the bronchial lymph nodes of mice exposed to respiratory allergen induced the development of T(R) cells, in a process that required T-cell costimulation via the inducible costimulator (ICOS-ICOS-ligand pathway. The T(R) cells produced IL-10, and had potent inhibitory activity; when adoptively transferred into sensitized mice, T(R) cells blocked the development of AHR. Both the development and the inhibitory function of regulatory cells were dependent on the presence of IL-10 and on ICOS-ICOS-ligand interactions. These studies demonstrate that T(R) cells and the ICOS-ICOS-ligand signaling pathway are critically involved in respiratory tolerance and in downregulating pulmonary inflammation in asthma.},
	keywords = {Allergens, Animals, Antigens, Antigens, Differentiation, T-Lymphocyte, Asthma, Bronchial Hyperreactivity, Bronchoalveolar Lavage Fluid, Inducible T-Cell Co-Stimulator Ligand, Inducible T-Cell Co-Stimulator Protein, Interleukin-10, Ligands, Mice, Mice, Inbred BALB C, Mice, Transgenic, Ovalbumin, Proteins, T-Lymphocytes},
	issn = {1078-8956},
	doi = {10.1038/nm745},
	author = {Akbari, Omid and Freeman, Gordon J and Meyer, Everett H and Greenfield, Edward A and Chang, Tammy T and Sharpe, Arlene H and Berry, Gerald and DeKruyff, Rosemarie H and Umetsu, Dale T}
}
@article {542731,
	title = {The B7-CD28 superfamily.},
	journal = {Nat Rev Immunol},
	volume = {2},
	number = {2},
	year = {2002},
	month = {2002 Feb},
	pages = {116-26},
	abstract = {The B7-1/B7-2-CD28/CTLA-4 pathway is crucial in regulating T-cell activation and tolerance. New B7 and CD28 molecules have recently been discovered and new pathways have been delineated that seem to be important for regulating the responses of previously activated T cells. Several B7 homologues are expressed on cells other than professional antigen-presenting cells, indicating new mechanisms for regulating T-cell responses in peripheral tissues. Some B7 homologues have unknown receptors, indicating that other immunoregulatory pathways remain to be described. Here, we summarize our current understanding of the new members of the B7 and CD28 families, and discuss their therapeutic potential.},
	keywords = {Animals, Antigens, CD, Antigens, CD28, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, Antigens, Differentiation, T-Lymphocyte, Antigens, Surface, Apoptosis Regulatory Proteins, Autoimmune Diseases, B-Lymphocytes, Cell Communication, Cell Differentiation, CTLA-4 Antigen, Humans, Immunoconjugates, Inducible T-Cell Co-Stimulator Protein, Lymphocyte Activation, Membrane Glycoproteins, Programmed Cell Death 1 Receptor, T-Lymphocytes},
	issn = {1474-1733},
	doi = {10.1038/nri727},
	author = {Sharpe, Arlene H and Freeman, Gordon J}
}
@article {542741,
	title = {CTLA-4 regulates cell cycle progression during a primary immune response.},
	journal = {Eur J Immunol},
	volume = {32},
	number = {2},
	year = {2002},
	month = {2002 Feb},
	pages = {366-73},
	abstract = {Engagement of CTLA-4 is critical for inhibiting T cell immune responses. Recent studies have shown that CTLA-4 plays a key role in regulating peripheral T cell tolerance. It has been suggested that one mechanism by which CTLA-4 performs this function is by regulating cell cycle progression. Here, we investigate in depth the role of CTLA-4 in regulating cell cycle progression in naive T cells by comparing the immune responses in the absence or presence of CTLA-4. In the absence of CLTA-4, T cells exhibit marked increases in T cell proliferation, IL-2 mRNA and protein secretion, and cells cycling in the S and G2-M phase. Analyses of cyclins, cyclin-dependent kinases, and cell cycle inhibitors involved in the transition from the G1 to S phase reveal that cell cycle progression is prolonged in the absence of CTLA-4. This is due to the early exit from the G1 phase, entry into the S phase, and prolonged S phase period. Re-expression of the cell cycle inhibitor p27(kip1) is delayed in the absence of CTLA-4. These studies demonstrate that the B7 : CTLA-4 pathway exerts its major effects on T cell immune responses via regulation of the cell cycle.},
	keywords = {Animals, Antigens, CD, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, Cell Cycle, Cell Cycle Proteins, CTLA-4 Antigen, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinases, Cyclins, Female, G1 Phase, Immunoconjugates, In Vitro Techniques, Interleukin-2, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Knockout, S Phase, T-Lymphocytes, Tumor Suppressor Proteins},
	issn = {0014-2980},
	doi = {10.1002/1521-4141(200202)32:2\&$\#$60;366::AID-IMMU366\&$\#$62;3.0.CO;2-5},
	author = {Greenwald, Rebecca J and Oosterwegel, Mariette A and van der Woude, Diane and Kubal, Anup and Mandelbrot, Didier A and Boussiotis, Vassiliki A and Sharpe, Arlene H}
}
@article {542746,
	title = {Cutting edge: inducible costimulator protein regulates both Th1 and Th2 responses to cutaneous leishmaniasis.},
	journal = {J Immunol},
	volume = {168},
	number = {3},
	year = {2002},
	month = {2002 Feb 1},
	pages = {991-5},
	abstract = {The CD28 family member inducible costimulator protein (ICOS) has an important role in T cell differentiation and Ig class switching. To investigate the role of ICOS in vivo, ICOS-/- mice were infected s.c. with Leishmania mexicana. While wild-type mice developed large, cutaneous lesions, the growth of lesions and tissue histopathology was significantly delayed in ICOS-/- mice. ICOS-/- mice exhibited marked decreases in both Th1 and Th2 cytokine production and profound defects in L. mexicana-specific Ig isotype class switching to IgG1 and IgG2a and reduced total IgE levels. Our findings indicate that ICOS is a key regulator of both Th1 and Th2 responses and has a role in controlling cutaneous L. mexicana infection.},
	keywords = {Animals, Antigens, Differentiation, T-Lymphocyte, Cytokines, Down-Regulation, Female, Immunoglobulin Class Switching, Inducible T-Cell Co-Stimulator Protein, Leishmania mexicana, Leishmaniasis, Cutaneous, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Knockout, Th1 Cells, Th2 Cells},
	issn = {0022-1767},
	author = {Greenwald, Rebecca J and McAdam, Alexander J and van der Woude, Diane and Satoskar, Abhay R and Sharpe, Arlene H}
}
@article {542721,
	title = {Memory Th2 effector cells can develop in the absence of B7-1/B7-2, CD28 interactions, and effector Th cells after priming with an intestinal nematode parasite.},
	journal = {J Immunol},
	volume = {168},
	number = {12},
	year = {2002},
	month = {2002 Jun 15},
	pages = {6344-51},
	abstract = {B7-1/B7-2 interactions are required for many Th2-cell mediated primary immune responses including the response that follows infection with the intestinal nematode parasite, Heligmosomoides polygyrus. However, few studies have examined the role of B7-1/B7-2/CD28 interactions in the development of a Th2 memory immune response. We examined the development of the memory Th2 response to H. polygyrus in BALB/c mice deficient in both B7-1 and B7-2 (B7-1/B7-2(-/-)) and in BALB/c mice deficient in CD28 (CD28(-/-)). Following primary inoculation with H. polygyrus, adult worms in the gut were cleared with an anti-helminthic drug and mice were subsequently challenge-inoculated with H. polygyrus larvae. The memory Th2 response is readily distinguished by its inhibitory effect on adult worm maturation, resulting in marked reductions in adult worm egg production that are not observed during the primary immune response. Following H. polygyrus challenge inoculation, comparable decreases in egg production and similar increases in mesenteric lymph node cell IL-4 production were observed in B7-1/B7-2(-/-) and B7-1/B7-2(+/+) mice. However, elevations in total serum IgG1 and IgE were reduced, while increases in serum Ag-specific IgG1 and IgE and germinal center formation were blocked in H. polygyrus-challenged B7-1/B7-2(-/-) mice. In contrast, in H. polygyrus-challenged CD28(-/-) mice, marked elevations in Ag-specific IgG1 and IgE and increased germinal center formation were observed. The results of these studies demonstrate that effector Th2 memory cells that produce IL-4 and mediate host defense can develop when B7-1/B7-2 interactions, and associated effector Th2 cell development, are blocked during priming. However, humoral immunity is impaired and differentially affected in B7-1/B7-2(-/-) mice and CD28(-/-) mice following H. polygyrus challenge.},
	keywords = {Animals, Antibody Specificity, Antigens, CD, Antigens, CD28, Antigens, CD80, Antigens, CD86, Cell Differentiation, Germinal Center, IgG Deficiency, Immunization, Immunization, Secondary, Immunoglobulin E, Immunoglobulins, Immunologic Memory, Interleukin-4, Intestinal Diseases, Parasitic, Lymphocytosis, Lymphopenia, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Knockout, Nematospiroides dubius, Parasite Egg Count, Strongylida Infections, T-Lymphocytes, Helper-Inducer, Th2 Cells},
	issn = {0022-1767},
	author = {Ekkens, Melinda J and Liu, Zhugong and Liu, Qian and Foster, Anthony and Whitmire, Jeannette and Pesce, John and Sharpe, Arlene H and Urban, Joseph F and Gause, William C}
}
@article {542726,
	title = {Negative co-receptors on lymphocytes.},
	journal = {Curr Opin Immunol},
	volume = {14},
	number = {3},
	year = {2002},
	month = {2002 Jun},
	pages = {391-6},
	abstract = {The past year has seen significant advances in our understanding of critical roles of negative immunoregulatory signals delivered through the B7-CD28 superfamily in regulating T cell activation and tolerance. Structural data on CTLA-4 have provided novel insights into the inhibitory functions of CTLA-4. Initial characterization of the PD-1-PD-1-ligand pathway has revealed that this pathway can downregulate TCR- and CD28-mediated signals. Recent studies indicate that ICOS exerts distinct effects at different phases of an immune response: ICOS can inhibit as well as stimulate T cell responses.},
	keywords = {Animals, Antigens, CD, Antigens, CD274, Antigens, CD28, Antigens, CD80, Antigens, Differentiation, Antigens, Differentiation, T-Lymphocyte, Antigens, Surface, Apoptosis Regulatory Proteins, Blood Proteins, CTLA-4 Antigen, Humans, Immunoconjugates, Inducible T-Cell Co-Stimulator Protein, Intercellular Signaling Peptides and Proteins, Membrane Glycoproteins, Peptides, Programmed Cell Death 1 Ligand 2 Protein, Programmed Cell Death 1 Receptor, T-Lymphocytes},
	issn = {0952-7915},
	author = {Greenwald, Rebecca J and Latchman, Yvette E and Sharpe, Arlene H}
}
@article {542736,
	title = {Role of the B7-CD28/CTLA-4 pathway in autoimmune disease.},
	journal = {Curr Dir Autoimmun},
	volume = {5},
	year = {2002},
	month = {2002},
	pages = {113-30},
	keywords = {Animals, Antibodies, Monoclonal, Antigens, CD, Antigens, CD28, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, Autoimmune Diseases, Autoimmunity, CTLA-4 Antigen, Diabetes Mellitus, Type 1, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Humans, Immune Tolerance, Immunoconjugates, Immunoglobulin G, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Mice, Transgenic, Multiple Sclerosis, Signal Transduction, T-Lymphocyte Subsets},
	issn = {1422-2132},
	author = {Chang, Tammy T and Kuchroo, Vijay K and Sharpe, Arlene H}
}
@article {542716,
	title = {T helper differentiation in resistant and susceptible B7-deficient mice infected with Leishmania major.},
	journal = {Eur J Immunol},
	volume = {32},
	number = {6},
	year = {2002},
	month = {2002 Jun},
	pages = {1764-72},
	abstract = {The contribution of the costimulatory molecules B7-1 and B7-2 to the in vivo differentiation of Th cells remains controversial. The infection of resistant and susceptible strains of mice with the parasite Leishmania major provides a well-established model for studying in vivo differentiation of CD4+ T cells. We have infected B7-1/B7-2-deficient mice on the BALB/c and 129 background with L. major and subsequently examined different parameters of infection and cytokine responses upon restimulation of lymph node cells in vitro. BALB/c B7-2-deficient and B7-1/B7-2-double deficient mice are resistant to L. major, whereas BALB/c B7-1-deficient mice remain as susceptible as wild-type BALB/c mice. Differential expression of B7-1 and B7-2 can explain the distinct roles observed for these B7 costimulators in L. major infection.},
	keywords = {Animals, Antigens, CD, Antigens, CD28, Antigens, CD80, Antigens, CD86, Cell Differentiation, Disease Susceptibility, Female, Immunoglobulin G, Interferon-gamma, Interleukin-4, Leishmania major, Leishmaniasis, Cutaneous, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, T-Lymphocytes, Helper-Inducer},
	issn = {0014-2980},
	doi = {10.1002/1521-4141(200206)32:6<1764::AID-IMMU1764>3.0.CO;2-V},
	author = {Brown, Julia A and Greenwald, Rebecca J and Scott, Sumi and Schweitzer, A Nicola and Satoskar, Abhay R and Chung, Charles and Schopf, Lisa R and van der Woude, Diane and Sypek, Joseph P and Sharpe, Arlene H}
}
@article {542671,
	title = {B7/CD28-dependent CD4+CD25+ regulatory T cells are essential components of the memory-protective immunity to Candida albicans.},
	journal = {J Immunol},
	volume = {169},
	number = {11},
	year = {2002},
	month = {2002 Dec 1},
	pages = {6298-308},
	abstract = {Protective immunity to the fungus Candida albicans is mediated by Ag-specific Th1 cells. Paradoxically, some Th2 cytokines are required for the maintenance of Th1-mediated immune resistance to the fungus. Therefore, in addition to the Th1/Th2 balance, other mechanisms seem to be involved in the regulation of Th1 immunity to the fungus. Here we show that CD4(+)CD25(+) T cells, negatively regulating antifungal Th1 reactivity, are generated in mice with candidiasis. CD4(+)CD25(+) T cells were not generated in B7-2- or CD28-deficient mice or in condition of IL-10 signaling deficiency. Accordingly, although capable of efficiently restricting the fungal growth, these mice experienced inflammatory pathology and were incapable of resistance to reinfection. CD4(+)CD25(+) T cells poorly proliferated in vitro; were highly enriched for cells producing IL-4, IL-10, and TGF-beta; and required IL-10-producing, Candida hypha-activated dendritic cells for generation. Adoptive transfer of CD4(+)CD25(+) T cells or IL-10-producing dendritic cells restored resistance to reinfection and decreased inflammation in B7-2-deficient mice. These results show that oral tolerance induced by Candida hyphae is required for the occurrence of long-lasting protective immunity after yeast priming. The implication is that preventing reactivation rather than favoring sterilizing immunity to ubiquitous fungal pathogens may represent the ultimate expectation of vaccine-based strategies.},
	keywords = {Adoptive Transfer, Animals, Antigens, CD, Antigens, CD28, Antigens, CD80, Antigens, CD86, Candida albicans, Candidiasis, CD4-Positive T-Lymphocytes, Cytokines, Dendritic Cells, Female, Immunologic Memory, In Vitro Techniques, Interleukin-10, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Knockout, Receptors, Interleukin-2, Signal Transduction, T-Lymphocyte Subsets, Th1 Cells, Th2 Cells},
	issn = {0022-1767},
	author = {Montagnoli, Claudia and Bacci, Angela and Bozza, Silvia and Gaziano, Roberta and Mosci, Paolo and Sharpe, Arlene H and Romani, Luigina}
}
@article {542676,
	title = {The CD154/CD40 interaction required for retrovirus-induced murine immunodeficiency syndrome is not mediated by upregulation of the CD80/CD86 costimulatory molecules.},
	journal = {J Virol},
	volume = {76},
	number = {24},
	year = {2002},
	month = {2002 Dec},
	pages = {13106-10},
	abstract = {C57BL/6 (B6) mice infected with LP-BM5 retroviruses develop disease, including an immunodeficiency similar to AIDS. This disease, murine AIDS (MAIDS), is inhibited by in vivo anti-CD154 monoclonal antibody treatment. The similar levels of insusceptibility of CD40(-/-) and CD154(-/-) B6 mice indicate that CD154/CD40 molecular interactions are required for MAIDS. CD4(+) T and B cells, respectively, provide the CD154 and CD40 expression needed for MAIDS induction. Here, the required CD154/CD40 interaction is shown to be independent of CD80 and CD86 expression: CD80/CD86(-/-) B6 mice develop MAIDS after LP-BM5 infection.},
	keywords = {Animals, Antigens, CD, Antigens, CD28, Antigens, CD40, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, CD40 Ligand, CTLA-4 Antigen, Disease Susceptibility, Immunoconjugates, Immunoglobulin G, Immunoglobulin M, Leukemia Virus, Murine, Membrane Glycoproteins, Mice, Mice, Knockout, Murine Acquired Immunodeficiency Syndrome, Retroviridae Infections, Up-Regulation},
	issn = {0022-538X},
	author = {Green, Kathy A and Cook, W James and Sharpe, Arlene H and Green, William R}
}
@article {542701,
	title = {CD80+Gr-1+ myeloid cells inhibit development of antifungal Th1 immunity in mice with candidiasis.},
	journal = {J Immunol},
	volume = {169},
	number = {6},
	year = {2002},
	month = {2002 Sep 15},
	pages = {3180-90},
	abstract = {To find out whether polymorphonuclear neutrophils (PMN), abundantly recruited in disseminated Candida albicans infection, could directly affect the activation of Th cells we addressed the issues as to whether murine PMN, like their human counterparts, express costimulatory molecules and the functional consequence of this expression in terms of antifungal immune resistance. To this purpose, we assessed 1) the expression of CD80 (B7-1) and CD86 (B7-2) molecules on peripheral, splenic, and inflammatory murine Gr-1+ PMN; 2) its modulation upon interaction with C. albicans in vitro, in vivo, and in human PMN; 3) the effect of Candida exposure on the ability of murine PMN to affect CD4+ Th1 cell proliferation and cytokine production; and 4) the mechanism responsible for this effect. Murine PMN constitutively expressed CD80 molecules on both the surface and intracellularly; however, in both murine and human PMN, CD80 expression was differentially modulated upon interaction with Candida yeasts or hyphae in vitro as well as in infected mice. The expression of the CD86 molecule was neither constitutive nor inducible upon exposure to the fungus. In vitro, Gr-1+ PMN were found to inhibit the activation of IFN-gamma-producing CD4+ T cells and to induce apoptosis through a CD80/CD28-dependent mechanism. A population of CD80+Gr-1+ myeloid cells was found to be expanded in conventional as well as in bone marrow-transplanted mice with disseminated candidiasis, but its depletion increased the IFN-gamma-mediated antifungal resistance. These data indicate that alternatively activated PMN expressing CD80 may adversely affect Th1-dependent resistance in fungal infections.},
	keywords = {Animals, Antigens, CD28, Antigens, CD80, Antigens, Differentiation, Myelomonocytic, Candida albicans, Candidiasis, CD4-Positive T-Lymphocytes, Cell Division, Cells, Cultured, Cytokines, Female, Humans, Immune Tolerance, Immunity, Innate, Interferon-gamma, Interleukin-10, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Knockout, Myeloid Cells, Neutrophils, Nitric Oxide, T-Lymphocytes, Regulatory, Th1 Cells},
	issn = {0022-1767},
	author = {Mencacci, Antonella and Montagnoli, Claudia and Bacci, Angela and Cenci, Elio and Pitzurra, Lucia and Spreca, Antonio and Kopf, Manfred and Sharpe, Arlene H and Romani, Luigina}
}
@article {542686,
	title = {Costimulatory molecule OX40L is critical for both Th1 and Th2 responses in allergic inflammation.},
	journal = {Eur J Immunol},
	volume = {32},
	number = {10},
	year = {2002},
	month = {2002 Oct},
	pages = {2874-80},
	abstract = {T cell activation and cytokine secretion are important mediators of inflammation in allergic asthma. The costimulatory pathway CD28/CD80/CD86 has been shown to play an important role in T cell activation in allergic asthma, but less is known about the effect of other costimulatory molecules in allergy. The costimulatory molecule OX40 ligand (OX40L), a member of the tumor necrosis factor superfamily, has been shown to be important in T cell priming and cytokine production. We investigated the role of OX40L in a murine model of allergic inflammation using OX40L(-/-) mice. In this model, following OVA sensitization and challenge, mice develop features of allergic inflammation including elevated levels of total serum IgE, pulmonary eosinophils, cytokines, and pulmonary inflammation. In the absence of OX40L, total serum IgE, pulmonary eosinophils, cytokines, and pulmonary inflammation were all significantly reduced compared to wild-type controls. Levels of eotaxin mRNA, an eosinophil-specific chemoattractant, were also markedly reduced, paralleling the significant reduction in pulmonary eosinophils. Levels of allergen-induced Th1 as well as Th2 cytokines were also significantly reduced. Together, the data support a critical role for OX40L signals in allergic responses.},
	keywords = {Animals, Antigens, CD, Antigens, CD28, Antigens, CD80, Antigens, CD86, Asthma, Cytokines, Eosinophils, Female, Hypersensitivity, Immunoglobulin E, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Ovalbumin, Th1 Cells, Th2 Cells, Tumor Necrosis Factors},
	issn = {0014-2980},
	doi = {10.1002/1521-4141(2002010)32:10<2874::AID-IMMU2874>3.0.CO;2-4},
	author = {Arestides, Ruth S S and He, Hongzhen and Westlake, Robert M and Chen, Andy I and Sharpe, Arlene H and Perkins, David L and Finn, Patricia W}
}
@article {542681,
	title = {Cutting edge: a crucial role for B7-CD28 in transmitting T help from APC to CTL.},
	journal = {J Immunol},
	volume = {169},
	number = {8},
	year = {2002},
	month = {2002 Oct 15},
	pages = {4094-7},
	abstract = {Although APC activation via CD40-CD40L signaling plays a critical role in enabling CD4(+) T cells to provide the "help" necessary for cross-priming of naive CTL, it is unclear how this makes the APC competent for priming. We have investigated the roles of B7-1/B7-2 and their receptors [corrected] CD28/CTLA-4 in cross-priming of CD4-dependent CTL in vivo. We find that both CD28 and B7-1/B7-2 are required for CD40-activated APC to cross-prime CTL, and that priming by CD40-activated APC was prevented by blockade of CD28. Conversely, augmenting CD28 signals with an agonistic Ab bypassed the requirement for CD4(+) T help or CD40 activation. Interestingly, blockade of the negative regulatory B7 receptor CTLA-4 failed to prime CTL in the absence of T help. These results support a model in which activation-induced up-regulation of B7 molecules on APC leads to increased CD28 signaling and a commitment to cross-priming of CD4-dependent CTL.},
	keywords = {Animals, Antigen-Presenting Cells, Antigens, CD, Antigens, CD28, Antigens, CD80, Antigens, CD86, Cell Line, Cytotoxicity, Immunologic, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, T-Lymphocytes, Cytotoxic, T-Lymphocytes, Helper-Inducer},
	issn = {0022-1767},
	author = {Prilliman, Kiley R and Lemmens, Edward E and Palioungas, Georgia and Wolfe, Thomas G and Allison, James P and Sharpe, Arlene H and Schoenberger, Stephen P}
}
@article {542691,
	title = {Cutting edge: CTLA-4 (CD152) differentially regulates mitogen-activated protein kinases (extracellular signal-regulated kinase and c-Jun N-terminal kinase) in CD4+ T cells from receptor/ligand-deficient mice.},
	journal = {J Immunol},
	volume = {169},
	number = {7},
	year = {2002},
	month = {2002 Oct 1},
	pages = {3475-9},
	abstract = {Although CTLA-4 (CD152) has potent inhibitory effects on T cell function, the signaling events affected by this coreceptor remain to be fully defined. Mitogen-activated protein kinases (MAPK) extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) act as crucial regulators of multiple aspects of cell function. Ab ligation studies have reported an inhibitory effect of CTLA-4 on TCR-induced ERK and JNK activation. In this study, we have re-examined the specificity of CTLA-4 inhibition of MAPKs by using natural ligand with ex vivo-purified CD4(+) T cells deficient in CD80 and CD86 (double knockout), or CTLA-4, CD80, and CD86 (triple knockout). Under these conditions, CTLA-4 ligation was found to up-regulate and sustain JNK activation, while inhibiting ERK activity. At the same time, JNK activation could not account for CTLA-4 induction of TGF-beta production. Our findings demonstrate that CTLA-4 cosignaling is more complex than previously appreciated, with an ability to differentially regulate members of the MAPK family in T cells.},
	keywords = {Animals, Antigens, CD, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, CD4-Positive T-Lymphocytes, Cells, Cultured, Coculture Techniques, CTLA-4 Antigen, Enzyme Activation, Enzyme Inhibitors, Enzyme Reactivators, Immunoconjugates, JNK Mitogen-Activated Protein Kinases, Ligands, MAP Kinase Signaling System, Membrane Glycoproteins, Mice, Mice, Knockout, Mitogen-Activated Protein Kinases, Up-Regulation},
	issn = {0022-1767},
	author = {Schneider, Helga and Mandelbrot, Didier A and Greenwald, Rebecca J and Ng, Fai and Lechler, Robert and Sharpe, Arlene H and Rudd, Christopher E}
}
@article {542696,
	title = {Genetic background determines the requirement for B7 costimulation in induction of autoimmunity.},
	journal = {Eur J Immunol},
	volume = {32},
	number = {9},
	year = {2002},
	month = {2002 Sep},
	pages = {2687-97},
	abstract = {B7 costimulatory molecules play an important role in inducing autoimmunity, tumor immunity, and transplant rejection, and therapeutic manipulation of B7 is being investigated in human diseases. To determine whether B7 costimulation is essential for inducing autoimmunity on different genetic backgrounds, we backcrossed B7.1/B7.2 deficient ((-/-)) mice on to the C57BL/6 (B6) and SJL backgrounds and induced experimental autoimmune encephalomyelitis (EAE) in these mice. B7.1/B7.2(-/-) mice on the B6 background were resistant to EAE induced with MOG 35-55, whereas the SJL B7.1/B7.2(-/-) mice were susceptible to PLP 139-151 or PLP 178-191-induced EAE. The SJL B7.1/B7.2(-/-) mice had a qualitatively different lesion pattern in that they showed increased white matter vacuolation compared to wild-type SJL mice when immunized with either PLP 139-151 or PLP 178-191. (B6xSJL)F1 B7.1/B7.2(+/+) mice were susceptible to EAE whereas (B6xSJL)F1 B7.1/B7.2(-/-) mice were resistant to EAE induced with either encephalitogenic peptide. Thus, genetic background determines the B7 requirement for inducing autoimmunity. These data have important implications for developing B7-based immunotherapies for human diseases.},
	keywords = {Amino Acid Sequence, Animals, Antigens, CD, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, Autoimmunity, Crosses, Genetic, CTLA-4 Antigen, Encephalomyelitis, Autoimmune, Experimental, Female, Genetic Predisposition to Disease, Glycoproteins, Immunization, Immunoconjugates, Lymph Nodes, Lymphocyte Activation, Male, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Myelin Proteolipid Protein, Myelin-Oligodendrocyte Glycoprotein, Peptide Fragments},
	issn = {0014-2980},
	doi = {10.1002/1521-4141(200209)32:9<2687::AID-IMMU2687>3.0.CO;2-1},
	author = {Jabs, Claudia and Greve, Bernhard and Chang, Tammy T and Sobel, Raymond A and Sharpe, Arlene H and Kuchroo, Vijay K}
}
@article {542666,
	title = {Nippostrongylus brasiliensis can induce B7-independent antigen-specific development of IL-4-producing T cells from naive CD4 T cells in vivo.},
	journal = {J Immunol},
	volume = {169},
	number = {12},
	year = {2002},
	month = {2002 Dec 15},
	pages = {6959-68},
	abstract = {Th2 immune responses to a number of infectious pathogens are dependent on B7-1/B7-2 costimulatory molecule interactions. We have now examined the Th2 immune response to Nippostrongylus brasiliensis (Nb) in B7-1/B7-2(-/-) mice and show that Th2 effector cells develop that can mediate worm expulsion and produce substantial Th2 cytokines comparable with wild-type infected mice; however, in marked contrast, B cell Ag-specific Ab production is abrogated after B7 blockade. To examine the mechanism of T cell activation, OVA-specific DO11.10 T cells were transferred to recipient mice, which were then immunized with a combination of Nb plus OVA or either alone. Only the combination of Nb plus OVA triggered T cell differentiation to OVA-specific Th2 cells, suggesting that Nb acts as an adjuvant to stimulate Ag-specific naive T cells to differentiate to effector Th2 cells. Furthermore, using the DO11.10 TCR-transgenic T cell adoptive transfer model, we show that blocking B7-1/B7-2 interactions does not impair nonparasite Ag-specific DO11.10 Th2 cell differentiation; however, DO11.10 T cell cycle progression and migration to the B cell zone are inhibited.},
	keywords = {Amino Acid Sequence, Animals, Antibodies, Helminth, Antigens, CD, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, B-Lymphocytes, Cell Cycle, Cell Differentiation, Cell Migration Inhibition, Cells, Cultured, CTLA-4 Antigen, Epitopes, T-Lymphocyte, Growth Inhibitors, Immunoconjugates, Immunosuppressive Agents, Injections, Subcutaneous, Interleukin-4, Interphase, Intestinal Mucosa, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Transgenic, Molecular Sequence Data, Nippostrongylus, Ovalbumin, Peptide Fragments, Strongylida Infections, T-Lymphocyte Subsets, Th2 Cells},
	issn = {0022-1767},
	author = {Liu, Zhugong and Liu, Qian and Pesce, John and Whitmire, Jeannette and Ekkens, Melinda J and Foster, Anthony and VanNoy, Jansie and Sharpe, Arlene H and Urban, Joseph F and Gause, William C}
}
@article {542706,
	title = {Protect the killer: CTLs need defenses against the tumor.},
	journal = {Nat Med},
	volume = {8},
	number = {8},
	year = {2002},
	month = {2002 Aug},
	pages = {787-9},
	keywords = {Animals, Antigens, CD, Antigens, CD274, Antigens, CD80, Antigens, Surface, Apoptosis, Apoptosis Regulatory Proteins, Blood Proteins, Humans, Membrane Glycoproteins, Mice, Models, Immunological, Neoplasms, Peptides, Programmed Cell Death 1 Receptor, T-Lymphocytes, Cytotoxic, Tumor Escape},
	issn = {1078-8956},
	doi = {10.1038/nm0802-787},
	author = {Freeman, Gordon J and Sharpe, Arlene H and Kuchroo, Vijay K}
}
@article {542776,
	title = {B7-dependent T-cell costimulation in mice lacking CD28 and CTLA4.},
	journal = {J Clin Invest},
	volume = {107},
	number = {7},
	year = {2001},
	month = {2001 Apr},
	pages = {881-7},
	abstract = {To examine whether B7 costimulation can be mediated by a molecule on T cells that is neither CD28 nor CTLA4, we generated mice lacking both of these receptors. CD28/CTLA4(-/-) mice resemble CD28(-/-) mice in having decreased expression of T-cell activation markers in vivo and decreased T-cell proliferation in vitro, as compared with wild-type mice. Using multiple approaches, we find B7-dependent costimulation in CD28/CTLA4(-/-) mice. The proliferation of CD28/CTLA4(-/-) T cells is inhibited by CTLA4-Ig and by the use of antigen-presenting cells lacking both B7-1 and B7-2. CD28/CTLA4(-/-) T-cell proliferation is increased by exposure to Chinese hamster ovary cells transfected with B7-1 or B7-2. Finally, administration of CTLA4-Ig to CD28/CTLA4(-/-) cardiac allograft recipients significantly prolongs graft survival. These data support the existence of an additional receptor for B7 molecules that is neither CD28 nor CTLA4.},
	keywords = {Animals, Antigens, CD, Antigens, CD28, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, Cell Division, CHO Cells, Cricetinae, CTLA-4 Antigen, Graft Rejection, Graft Survival, Heart Transplantation, Immunoconjugates, Immunophenotyping, Interferon-gamma, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, T-Lymphocytes, Th1 Cells, Transplantation, Homologous},
	issn = {0021-9738},
	doi = {10.1172/JCI11710},
	author = {Mandelbrot, D A and Oosterwegel, M A and Shimizu, K and Yamada, A and Freeman, G. J. and Mitchell, R N and Sayegh, M H and Sharpe, A. H.}
}
@article {542781,
	title = {CTLA-4 regulates induction of anergy in vivo.},
	journal = {Immunity},
	volume = {14},
	number = {2},
	year = {2001},
	month = {2001 Feb},
	pages = {145-55},
	abstract = {The requirement for CTLA-4 during the induction of peripheral T cell tolerance in vivo was investigated using naive TCR transgenic T cells lacking CTLA-4. CTLA-4(-/-) T cells are resistant to tolerance induction, as demonstrated by their proliferative responses, IL-2 production, and progression into the cell cycle. Following exposure to a tolerogenic stimulus in vivo and restimulation in vitro, wild-type T cells are blocked at the late G1 to S restriction point of the cell cycle. In contrast, CTLA-4(-/-) T cells enter into the S phase of the cell cycle, as shown by downregulation of p27(kip1), elevated cdk2 kinase activity, and Rb hyperphosphorylation. Thus, CTLA-4 has an essential role in determining the outcome of T cell encounter with a tolerogenic stimulus.},
	keywords = {Animals, Antigens, CD, Antigens, Differentiation, Apoptosis, Cell Cycle, Clonal Anergy, CTLA-4 Antigen, Cytokines, DNA-Binding Proteins, Immune Tolerance, Immunoconjugates, In Vitro Techniques, Interleukin-2, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Transgenic, T-Lymphocytes},
	issn = {1074-7613},
	author = {Greenwald, R J and Boussiotis, V. A. and Lorsbach, R B and Abbas,A.K. and Sharpe, A. H.}
}
@article {542766,
	title = {ICOS is critical for CD40-mediated antibody class switching.},
	journal = {Nature},
	volume = {409},
	number = {6816},
	year = {2001},
	month = {2001 Jan 4},
	pages = {102-5},
	abstract = {The inducible co-stimulatory molecule (ICOS) is a CD28 homologue implicated in regulating T-cell differentiation. Because co-stimulatory signals are critical for regulating T-cell activation, an understanding of co-stimulatory signals may enable the design of rational therapies for immune-mediated diseases. According to the two-signal model for T-cell activation, T cells require an antigen-specific signal and a second, co-stimulatory, signal for optimal T-cell activation. The co-stimulatory signal promotes T-cell proliferation, lymphokine secretion and effector function. The B7-CD28 pathway provides essential signals for T-cell activation, but does not account for all co-stimulation. We have generated mice lacking ICOS (ICOS-/- ) to determine the essential functions of ICOS. Here we report that ICOS-/- mice exhibit profound deficits in immunoglobulin isotype class switching, accompanied by impaired germinal centre formation. Class switching was restored in ICOS-/- mice by CD40 stimulation, showing that ICOS promotes T-cell/B-cell collaboration through the CD40/CD40L pathway.},
	keywords = {Animals, Antibody Formation, Antigens, CD40, Antigens, Differentiation, T-Lymphocyte, B-Lymphocytes, CD4-Positive T-Lymphocytes, CD40 Ligand, Gene Targeting, Germinal Center, Hemocyanin, Immunoglobulin Class Switching, Immunoglobulin Isotypes, Inducible T-Cell Co-Stimulator Protein, Mice, T-Lymphocytes},
	issn = {0028-0836},
	doi = {10.1038/35051107},
	author = {McAdam, A J and Greenwald, R J and Levin, M A and Chernova, T and Malenkovich, N and Ling, V and Freeman, G. J. and Sharpe, A. H.}
}
@article {542786,
	title = {PD-L2 is a second ligand for PD-1 and inhibits T cell activation.},
	journal = {Nat Immunol},
	volume = {2},
	number = {3},
	year = {2001},
	month = {2001 Mar},
	pages = {261-8},
	abstract = {Programmed death I (PD-I)-deficient mice develop a variety of autoimmune-like diseases, which suggests that this immunoinhibitory receptor plays an important role in tolerance. We identify here PD-1 ligand 2 (PD-L2) as a second ligand for PD-1 and compare the function and expression of PD-L1 and PD-L2. Engagement of PD-1 by PD-L2 dramatically inhibits T cell receptor (TCR)-mediated proliferation and cytokine production by CD4+ T cells. At low antigen concentrations, PD-L2-PD-1 interactions inhibit strong B7-CD28 signals. In contrast, at high antigen concentrations, PD-L2-PD-1 interactions reduce cytokine production but do not inhibit T cell proliferation. PD-L-PD-1 interactions lead to cell cycle arrest in G0/G1 but do not increase cell death. In addition, ligation of PD-1 + TCR leads to rapid phosphorylation of SHP-2, as compared to TCR ligation alone. PD-L expression was up-regulated on antigen-presenting cells by interferon gamma treatment and was also present on some normal tissues and tumor cell lines. Taken together, these studies show overlapping functions of PD-L1 and PD-L2 and indicate a key role for the PD-L-PD-1 pathway in regulatingT cell responses.},
	keywords = {Amino Acid Sequence, Animals, Antigens, CD, Antigens, CD274, Antigens, CD28, Antigens, CD80, Antigens, Surface, Apoptosis, Apoptosis Regulatory Proteins, Blood Proteins, Cells, Cultured, CHO Cells, Cricetinae, Cytokines, Humans, Intercellular Signaling Peptides and Proteins, Jurkat Cells, Ligands, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Molecular Sequence Data, Peptides, Programmed Cell Death 1 Ligand 2 Protein, Programmed Cell Death 1 Receptor, Receptors, Antigen, T-Cell, Sequence Homology, Amino Acid, T-Lymphocytes, Transfection},
	issn = {1529-2908},
	doi = {10.1038/85330},
	author = {Latchman, Y and Wood, C. R. and Chernova, T and Chaudhary, D and Borde, M and Chernova, I and Iwai, Y and Long, A J and Brown, J A and Nunes, R and Greenfield, E A and Bourque, K and Boussiotis, V. A. and Carter, L L and Carreno, B M and Malenkovich, N and Nishimura, H and Okazaki, T and Honjo, T and Sharpe, A. H. and Freeman, G. J.}
}
@article {542761,
	title = {Requirement of CDC45 for postimplantation mouse development.},
	journal = {Mol Cell Biol},
	volume = {21},
	number = {14},
	year = {2001},
	month = {2001 Jul},
	pages = {4598-603},
	abstract = {CDC45 is required for the initiation of DNA replication in Saccharomyces cerevisiae and functions as a DNA polymerase alpha loading factor in Xenopus, but its role in mammalian DNA replication is unknown. To investigate the genetic and physiological functions of CDC45, we used a gene targeting strategy to generate mice lacking a functional CDC45 gene. Homozygous mutant mice lacking a functional CDC45 gene underwent uterine implantation and induced uterine decidualization but did not develop substantially thereafter. Detailed analysis of CDC45 null embryos cultured in vitro revealed impaired proliferation of the inner cell mass. These findings make CDC45 the only putative replication factor experimentally proven to be essential for mammalian development. The CDC45 gene localizes to human chromosome 22q11.2 in the DiGeorge syndrome critical region (DGCR). Almost 90\% of individuals with congenital cardiac and craniofacial defects have a monoallelic deletion in the DGCR that includes CDC45. We report here that heterozygous mutant mice develop into adulthood without any apparent abnormalities, so that it is unlikely that hemizygosity of CDC45 alone is responsible for the cardiac and craniofacial defects in the congenital syndromes.},
	keywords = {Animals, Blastocyst, Cell Cycle Proteins, Embryonic and Fetal Development, Embryonic Development, Female, Gene Targeting, Humans, Male, Mice, Mice, Knockout, Phenotype, Pregnancy},
	issn = {0270-7306},
	doi = {10.1128/MCB.21.14.4598-4603.2001},
	author = {Yoshida, K and Kuo, F and George, E L and Sharpe, A. H. and Dutta, A}
}
@article {542771,
	title = {SAP controls T cell responses to virus and terminal differentiation of TH2 cells.},
	journal = {Nat Immunol},
	volume = {2},
	number = {5},
	year = {2001},
	month = {2001 May},
	pages = {410-4},
	abstract = {SH2D1A, which encodes signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), is altered in patients with X-linked lymphoproliferative disease (XLP), a primary immunodeficiency. SAP-deficient mice infected with lymphocytic choriomeningitis virus had greatly increased numbers of CD8+ and CD4+ interferon-gamma-producing spleen and liver cells compared to wild-type mice. The immune responses of SAP-deficient mice to infection with Leishmania major together with in vitro studies showed that activated SAP-deficient T cells had an impaired ability to differentiate into T helper 2 cells. The aberrant immune responses in SAP-deficient mice show that SAP controls several distinct key T cell signal transduction pathways, which explains in part the complexity of the XLP phenotypes.},
	keywords = {Animals, Carrier Proteins, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Differentiation, Cytokines, Immunoglobulin E, Interferon-gamma, Intracellular Signaling Peptides and Proteins, Leishmaniasis, Cutaneous, Liver, Lymphocytic Choriomeningitis, Lymphoproliferative Disorders, Mice, Mice, Mutant Strains, Signal Transduction, Spleen, T-Lymphocytes, Th2 Cells},
	issn = {1529-2908},
	doi = {10.1038/87713},
	author = {Wu, C. and Nguyen, K B and Pien, G C and Wang, N. and Gullo, C and Howie, D and Sosa, M R and Edwards, M J and Borrow, P and Satoskar, A R and Sharpe, A. H. and Biron, C A and Terhorst, C.}
}
@article {542756,
	title = {CD28-independent costimulation of T cells in alloimmune responses.},
	journal = {J Immunol},
	volume = {167},
	number = {1},
	year = {2001},
	month = {2001 Jul 1},
	pages = {140-6},
	abstract = {T cell costimulation by B7 molecules plays an important role in the regulation of alloimmune responses. Although both B7-1 and B7-2 bind CD28 and CTLA-4 on T cells, the role of B7-1 and B7-2 signaling through CTLA-4 in regulating alloimmune responses is incompletely understood. To address this question, we transplanted CD28-deficient mice with fully allogeneic vascularized cardiac allografts and studied the effect of selective blockade of B7-1 or B7-2. These mice reject their grafts by a mechanism that involves both CD4(+) and CD8(+) T cells. Blockade of CTLA-4 or B7-1 significantly accelerated graft rejection. In contrast, B7-2 blockade significantly prolonged allograft survival and, unexpectedly, reversed the acceleration of graft rejection caused by CTLA-4 blockade. Furthermore, B7-2 blockade prolonged graft survival in recipients that were both CD28 and CTLA-4 deficient. Our data indicate that B7-1 is the dominant ligand for CTLA-4-mediated down-regulation of alloimmune responses in vivo and suggest that B7-2 has an additional receptor other than CD28 and CTLA-4 to provide a positive costimulatory signal for T cells.},
	keywords = {Animals, Antibodies, Blocking, Antigens, CD, Antigens, CD28, Antigens, CD80, Antigens, Differentiation, CTLA-4 Antigen, Graft Rejection, Heart Transplantation, Immune Sera, Immunoconjugates, Injections, Intraperitoneal, Isoantigens, Lymphocyte Activation, Lymphocyte Culture Test, Mixed, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes},
	issn = {0022-1767},
	author = {Yamada, A and Kishimoto, K and Dong, V M and Ho, MS and Salama, A D and Anosova, N G and Benichou, G and Mandelbrot, D A and Sharpe, A. H. and Turka, L A and Auchincloss, H and Sayegh, M H}
}
@article {542751,
	title = {Rejection of mouse cardiac allografts by costimulation in trans.},
	journal = {J Immunol},
	volume = {167},
	number = {3},
	year = {2001},
	month = {2001 Aug 1},
	pages = {1174-8},
	abstract = {The activation of T cells by B7 costimulation in trans has been demonstrated in vitro, but the in vivo relevance is unknown. To study costimulation in trans of CD4(+) T cells in vivo, we performed cardiac transplants from B7-1/B7-2-deficient mice to recipients that do not express MHC class II molecules on peripheral APCs, but do have functional CD4(+) T cells (II(-)/4(+) mice). This model restricts the B7-dependent activation of CD4(+) T cells to costimulation in trans and excludes any contribution from indirect Ag presentation. We find that II(-)/4(+) recipients reject B7-deficient grafts as rapidly as wild-type grafts, suggesting that costimulation in trans can mediate rejection as potently as costimulation in cis. Treatment of II(-)/4(+) recipients of B7-deficient grafts with depleting Abs to CD4 or CD8 demonstrates that indirect Ag presentation to CD8(+) cells does not significantly contribute to rejection. This is the first demonstration that costimulation in trans can mediate an immune response in vivo and has important therapeutic implications.},
	keywords = {Animals, Antigen-Presenting Cells, Antigens, CD, Antigens, CD4, Antigens, CD80, Antigens, CD86, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cells, Cultured, Graft Rejection, Heart Transplantation, Histocompatibility Antigens Class II, Lymphocyte Activation, Lymphocyte Culture Test, Mixed, Male, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Transplantation, Homologous},
	issn = {0022-1767},
	author = {Mandelbrot, D A and Kishimoto, K and Auchincloss, H and Sharpe, A. H. and Sayegh, M H}
}
@article {542866,
	title = {B7 costimulation is critical for antibody class switching and CD8(+) cytotoxic T-lymphocyte generation in the host response to vesicular stomatitis virus.},
	journal = {J Virol},
	volume = {74},
	number = {1},
	year = {2000},
	month = {2000 Jan},
	pages = {203-8},
	abstract = {Antibody and cytotoxic T-lymphocyte (CTL) responses have critical roles in eliminating many viral infections. In addition to stimulation of the T-cell receptor, T cells require costimulatory signals to respond optimally. We evaluated the role of B7 costimulatory molecules (B7-1 and B7-2) in the immune response to viral infection using vesicular stomatitis virus (VSV) and mice lacking either B7-1 or B7-2 or both molecules. Mice lacking both B7-1 and B7-2 had essentially no anti-VSV immunoglobulin G1 (IgG1) response, decreased IgG2a responses, and normal IgM responses, while mice lacking either B7-1 or B7-2 had unaltered anti-VSV antibody responses compared to wild-type mice. Depletion of CD4(+) cells further reduced the IgG2a response in mice lacking both B7 molecules, suggesting that CD4(-) cells may supply help for IgG2a in the absence of B7 costimulation. The absence of both B7 molecules profoundly reduced generation of both primary and secondary VSV-specific class I major histocompatibility complex (MHC)-restricted CTL, whereas VSV-specific CTL responses in mice lacking either B7-1 or B7-2 were similar to those of wild-type animals. Class I MHC-restricted CTL in wild-type mice were not dependent on CD4(+) cells, suggesting that the failure of CTL in the absence of B7s is due to a lack of B7 costimulation directly to the CD8(+) CTL. These data demonstrate that B7-1 and B7-2 have critical, overlapping functions in the antibody and CTL responses to this viral infection.},
	keywords = {Animals, Antibodies, Viral, Antigens, CD, Antigens, CD80, Antigens, CD86, Membrane Glycoproteins, Mice, Mice, Knockout, T-Lymphocytes, Cytotoxic, Vesicular stomatitis Indiana virus},
	issn = {0022-538X},
	author = {McAdam, A J and Farkash, E A and Gewurz, B E and Sharpe, A. H.}
}
@article {542826,
	title = {Association of B7-1 co-stimulation with the development of graft arterial disease. Studies using mice lacking B7-1, B7-2, or B7-1/B7-2.},
	journal = {Am J Pathol},
	volume = {157},
	number = {2},
	year = {2000},
	month = {2000 Aug},
	pages = {473-84},
	abstract = {To investigate the roles of B7-1 and/or B7-2 co-stimulatory molecule in the development of graft arterial disease (GAD), major histocompatibility complex (MHC) class II-mismatched allograft hearts were transplanted into wild-type, B7-1(-/-), B7-2(-/-), or B7-1/B7-2(-/-) recipient mice. Grafts were explanted at 4 or 8 weeks and used for histological and immunohistochemical analyses, RNase protection assay, and flow cytometry of graft infiltrating cells. Grafts in wild-type recipients showed macrophage, recipient MHC class II, and B7 molecule co-localization by immunohistochemistry to GAD lesions. Flow cytometry revealed that CD11b(+) and MHC class II(+) graft infiltrating cells expressed B7-1 more than B7-2, whereas B7-2 expression was predominant in CD11b(-) cells at 4 and 8 weeks. GAD was significantly attenuated in the allografts in B7-1(-/-) and B7-1/B7-2(-/-) but not in B7-2(-/-) recipients compared to wild-type hosts. Interferon-gamma mRNA levels were comparable in all graft combinations, whereas interleukin-4 mRNA levels decreased in grafts in B7-2 deficient hosts, but did not correlate with GAD attenuation. The findings indicate distinct roles for B7-1 and B7-2 co-stimulatory molecules in the development of GAD, potentially because of differential expression of B7-1 and B7-2 molecules on distinct stimulator and/or effector cell populations.},
	keywords = {Animals, Antigen-Presenting Cells, Antigens, CD, Antigens, CD80, Antigens, CD86, B-Lymphocytes, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Chemokines, Cytokines, Female, Flow Cytometry, Gene Expression Regulation, Genotype, Graft Occlusion, Vascular, Graft Rejection, Heart Transplantation, Histocompatibility Antigens Class II, Immunohistochemistry, Macrophages, Male, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Time Factors, Transplantation, Homologous},
	issn = {0002-9440},
	doi = {10.1016/S0002-9440(10)64559-2},
	author = {Furukawa, Y and Mandelbrot, D A and Libby, P and Sharpe, A. H. and Mitchell, R N}
}
@article {542816,
	title = {Autoantibody responses and pathology regulated by B7-1 and B7-2 costimulation in MRL/lpr lupus.},
	journal = {J Immunol},
	volume = {165},
	number = {6},
	year = {2000},
	month = {2000 Sep 15},
	pages = {3436-43},
	abstract = {The activation of T lymphocytes requires both Ag-mediated signaling through the TCR as well as costimulatory signals transmitted through B7-1 and/or B7-2 with CD28. The interference of B7-mediated costimulatory signals has been proposed as one immunotherapeutic intervention for the prevention autoimmune disease. This study has examined autoantibody responses and autoimmune pathology in a murine model of human systemic lupus erythematosus (SLE), the MRL-lpr/lpr mouse, genetically deficient in B7-1 or B7-2, or in mice treated with B7-1/B7-2 blocking Abs. In contrast to other studies of murine models of SLE, MRL-lpr/lpr mice treated with B7 blocking Abs exhibit strong anti-small nuclear ribonucleoprotein (snRNP) and anti-DNA autoantibody responses with some changes in isotype switching as compared with untreated animals. All MRL-lpr/lpr mice deficient in B7-1 or B7-2 produce anti-snRNP and anti-DNA titers with isotypes virtually identical with wild-type animals. However, the absence of B7-2 costimulation did interfere with the spontaneous activation and the accumulation of memory CD4+ or CD8+ T lymphocytes characteristic of wild-type MRL-lpr/lpr mice. IgG and C3 complement deposition was less pronounced in the kidneys of B7-2 deficient MRL-lpr/lpr mice, reflecting their lessor degree of glomerulonephritis. By comparison, B7-1-deficient MRL-lpr/lpr mice had more severe IgG and C3 deposits in glomeruli.},
	keywords = {Animals, Antibodies, Antinuclear, Antigens, CD, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, B-Lymphocyte, Autoantibodies, Biological Markers, Complement C3, DNA, Immunoglobulin G, Immunoglobulin Isotypes, Immunoglobulin M, Kidney, Lupus Nephritis, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Inbred MRL lpr, Mice, Knockout, Ribonucleoproteins, Small Nuclear, T-Lymphocytes},
	issn = {0022-1767},
	author = {Liang, B and Kashgarian, M J and Sharpe, A. H. and Mamula, M J}
}
@article {542811,
	title = {B7 co-stimulatory requirements differ for induction of immune responses by DNA, protein and recombinant pox virus vaccination.},
	journal = {Eur J Immunol},
	volume = {30},
	number = {9},
	year = {2000},
	month = {2000 Sep},
	pages = {2650-9},
	abstract = {Whether B7-1 and B7-2 have distinct functions for eliciting immune responses to antigens that are presented to the immune system by intracellular and extracellular antigen processing pathways is an unresolved question. To investigate this issue we compared the humoral and cellular immune responses elicited by immunizing wild-type, B7-1-/- and B7-2-/- mice with either HIV-1 gp120 plasmid DNA, recombinant gp120 protein or vaccinia virus expressing gp120. The generation of both humoral and cellular immune responses to an antigen produced intracellularly following DNA vaccination had critical requirements for B7-2, but not B7-1. Neither of the molecules was essential for the generation of antibody responses to an extracellular protein antigen administered with adjuvant; B7-1 had little effect on the elicited immune responses. When recombinant vaccinia virus was used to present antigen intracellularly in the context of a viral infection, B7-2 was absolutely required for antibody and T cell proliferative responses, but it exerted a suppressive effect on the elicited CTL activity. These results demonstrate that antigens presented to the immune system by different mechanisms have distinct B7-1 and B7-2 co-stimulatory requirements.},
	keywords = {AIDS Vaccines, Animals, Antigens, CD, Antigens, CD80, Antigens, CD86, Female, HIV Envelope Protein gp120, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, T-Lymphocytes, Cytotoxic, Vaccination, Vaccines, DNA, Vaccines, Synthetic, Vaccinia virus},
	issn = {0014-2980},
	doi = {10.1002/1521-4141(200009)30:9<2650::AID-IMMU2650>3.0.CO;2-K},
	author = {Santra, S and Barouch, D H and Sharpe, A. H. and Letvin, N L}
}
@article {542836,
	title = {Costimulation by B7-1 and B7-2 is required for autoimmune disease in MRL-Faslpr mice.},
	journal = {J Immunol},
	volume = {164},
	number = {11},
	year = {2000},
	month = {2000 Jun 1},
	pages = {6046-56},
	abstract = {Autoimmune lupus nephritis is dependent on infiltrating autoreactive leukocytes and Igs. B7 costimulatory molecules (B7-1 and B7-2) provide signals essential for T cell activation and Ig class switching. In MRL-Faslpr mice, a model of human lupus, although multiple tissues are targeted for autoimmune injury, nephritis is fatal. We identified intrarenal B7-1 and B7-2 expression, restricted to kidney-infiltrating leukocytes, before and increasing with progressive nephritis in MRL-Faslpr mice. Thus, we hypothesized that the B7 pathway is required for autoimmune disease in MRL-Faslpr mice. To investigate the role of B7 costimulatory molecules in this autoimmune disease, we generated a MRL-Faslpr strain deficient in B7-1 and B7-2. Strikingly, MRL-Faslpr mice lacking both B7 costimulators do not develop kidney (glomerular, tubular, interstitial, vascular) pathology, or proteinuria, and survive far longer. Intrarenal downstream effector transcripts (IFN-gamma, IL-12, monocyte chemoattractant protein-1, CSF-1) linked to nephritis remained at normal levels compared with wild-type mice. Skin lesions and lymphoid enlargement characteristic of MRL-Faslpr mice were diminished in B7-1/B7-2-deficient MRL-Faslpr mice. B7-1/B7-2-deficient MRL-Faslpr mice did not develop leukocytic infiltrates, elevated serum IgG and isotypes (G1,G2b,G3), autoantibodies, and intrarenal IgG deposits. Our findings demonstrate that B7-1 and B7-2 costimulatory pathways are critical to the pathogenesis of autoimmune lupus.},
	keywords = {Animals, Antibodies, Antinuclear, Antigens, CD, Antigens, CD80, Antigens, CD86, Autoimmune Diseases, Cell Movement, Chemokines, Cytokines, Disease Progression, Immunoglobulin G, Kidney Glomerulus, Leukocytes, Lung, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Inbred MRL lpr, Mice, Knockout, Nephritis, Proteinuria, Species Specificity, Survival Analysis, Up-Regulation},
	issn = {0022-1767},
	author = {Kinoshita, K and Tesch, G and Schwarting, A and Maron, R and Sharpe, A. H. and Kelley, V R}
}
@article {542856,
	title = {Differential glycosylation of the Cas-Br-E env protein is associated with retrovirus-induced spongiform neurodegeneration.},
	journal = {J Virol},
	volume = {74},
	number = {3},
	year = {2000},
	month = {2000 Feb},
	pages = {1558-65},
	abstract = {The wild mouse ecotropic retrovirus, Cas-Br-E, induces progressive, noninflammatory spongiform neurodegenerative disease in susceptible mice. Functional genetic analysis of the Cas-Br-E genome indicates that neurovirulence maps to the env gene, which encodes the surface glycoprotein responsible for binding and fusion of virus to host cells. To understand how the envelope protein might be involved in the induction of disease, we examined the regional and temporal expression of Cas-Br-E Env protein in the central nervous systems (CNS) of mice infected with the highly neurovirulent chimeric virus FrCas(E). We observed that multiple isoforms of Cas-Br-E Env were expressed in the CNS, with different brain regions exhibiting unique patterns of processed Env glycoprotein. Specifically, the expression of gp70 correlated with regions showing microglial infection and spongiform neurodegeneration. In contrast, regions high in neuronal infection and without neurodegenerative changes (the cerebellum and olfactory bulb) were characterized by a gp65 Env protein isoform. Sedimentation analysis of brain region extracts indicated that gp65 rather than gp70 was incorporated into virions. Biochemical analysis of the Cas-Br-E Env isoforms indicated that they result from differential processing of N-linked sugars. Taken together, these results indicate that differential posttranslational modification of the Cas-Br-E Env is associated with a failure to incorporate certain Env isoforms into virions in vivo, suggesting that defective viral assembly may be associated with the induction of spongiform neurodegeneration.},
	keywords = {Animals, Brain, Gammaretrovirus, Glycosylation, Mice, Protein Isoforms, Retroviridae Infections, Viral Envelope Proteins},
	issn = {0022-538X},
	author = {Lynch, W P and Sharpe, A. H.}
}
@article {542821,
	title = {Either B7 costimulation or IL-2 can elicit generation of primary alloreactive CTL.},
	journal = {J Immunol},
	volume = {165},
	number = {6},
	year = {2000},
	month = {2000 Sep 15},
	pages = {3088-93},
	abstract = {B7-1 and B7-2 are important costimulatory molecules in the activation of T cell immunity. We have used mice made genetically deficient in either or both B7 molecules to determine the role of B7 molecules in activation of primary alloreactive CTL. The absence of either B7-1 or B7-2 did not alter generation of CTL from unfractionated lymphocytes, but the absence of B7-2 greatly decreased CTL generation from purified CD8+ responder cells. However, if B7-1 was induced on the stimulating cells then CTL generation was restored to wild-type levels. Absence of both B7-1 and B7-2 from MLR using whole splenocytes resulted in a profound reduction in generation of CTL. This could completely be reversed by the addition of IL-2. B7 molecules could directly costimulate CD8+ cells, as purified CD8+ cells developed into mature CTL when stimulated with wild-type APC, but not with B7-deficient APC. Again, IL-2 could drive CTL generation from purified CD8+ cells, even in the absence of B7 molecules. Taken together, these results demonstrate an important role for B7 costimulation in CTL generation.},
	keywords = {Animals, Antigens, CD, Antigens, CD28, Antigens, CD80, Antigens, CD86, CD8-Positive T-Lymphocytes, Cell Differentiation, Cytotoxicity Tests, Immunologic, Cytotoxicity, Immunologic, Interleukin-2, Lymphocyte Activation, Lymphocyte Culture Test, Mixed, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Inbred Strains, Mice, Knockout, Spleen, Stem Cells, T-Lymphocytes, Cytotoxic},
	issn = {0022-1767},
	author = {McAdam, A J and Gewurz, B E and Farkash, E A and Sharpe, A. H.}
}
@article {542831,
	title = {Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice.},
	journal = {Mol Cell Biol},
	volume = {20},
	number = {15},
	year = {2000},
	month = {2000 Aug},
	pages = {5479-89},
	abstract = {Protein-tyrosine phosphatase 1B (PTP-1B) is a major protein-tyrosine phosphatase that has been implicated in the regulation of insulin action, as well as in other signal transduction pathways. To investigate the role of PTP-1B in vivo, we generated homozygotic PTP-1B-null mice by targeted gene disruption. PTP-1B-deficient mice have remarkably low adiposity and are protected from diet-induced obesity. Decreased adiposity is due to a marked reduction in fat cell mass without a decrease in adipocyte number. Leanness in PTP-1B-deficient mice is accompanied by increased basal metabolic rate and total energy expenditure, without marked alteration of uncoupling protein mRNA expression. In addition, insulin-stimulated whole-body glucose disposal is enhanced significantly in PTP-1B-deficient animals, as shown by hyperinsulinemic-euglycemic clamp studies. Remarkably, increased insulin sensitivity in PTP-1B-deficient mice is tissue specific, as insulin-stimulated glucose uptake is elevated in skeletal muscle, whereas adipose tissue is unaffected. Our results identify PTP-1B as a major regulator of energy balance, insulin sensitivity, and body fat stores in vivo.},
	keywords = {Adipose Tissue, Animals, Body Weight, Carrier Proteins, Energy Metabolism, Female, Glucose, Glucose Tolerance Test, Homeostasis, Hyperinsulinism, Insulin Resistance, Ion Channels, Leptin, Male, Membrane Proteins, Membrane Transport Proteins, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Mitochondrial Proteins, Muscle, Skeletal, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Protein Tyrosine Phosphatases, Proteins, RNA, Messenger},
	issn = {0270-7306},
	author = {Klaman, L D and Boss, O and Peroni, O D and Kim, J K and Martino, J L and Zabolotny, J M and Moghal, N and Lubkin, M and Kim, Y B and Sharpe, A. H. and Stricker-Krongrad, A and Shulman, G I and Neel, B G and Kahn, B B}
}
@article {542846,
	title = {Prevention and treatment of factor VIII inhibitors in murine hemophilia A.},
	journal = {Blood},
	volume = {95},
	number = {4},
	year = {2000},
	month = {2000 Feb 15},
	pages = {1324-9},
	abstract = {Inhibitory antibody formation is a major complication of factor VIII replacement therapy in patients with hemophilia A. To better understand the pathogenesis of this immunologic reaction, we evaluated the role of T-cell costimulatory signals for antifactor VIII antibody formation in a murine model of hemophilia A. Repeated intravenous injections of factor VIII in these factor VIII-deficient mice induced an antifactor VIII inhibitor antibody response. This response was shown to be T-cell dependent by its absence in hemophilic mice also deficient for the T-cell costimulatory ligand B7-2. In separate experiments, injection of murine CTLA4-Ig completely blocked the primary response to factor VIII in hemophilic mice with intact B7 function. This reagent also prevented or diminished further increases in antifactor VIII when given to hemophilic mice with low antifactor VIII antibody titers. These studies suggest that strategies targeting the B7-CD28 pathway are potential therapies to prevent and treat inhibitory antifactor VIII antibodies. Moreover, because the development of antibodies to replaced proteins may limit the success of many human gene therapy approaches, our results may be broadly applicable. (Blood. 2000;95:1324-1329)},
	keywords = {Animals, Antibody Formation, Antigens, CD, Antigens, CD86, Antigens, Differentiation, Autoantibodies, CTLA-4 Antigen, Factor VIII, Female, Hemophilia A, Humans, Immunoconjugates, Immunosuppressive Agents, Lymphocyte Activation, Male, Membrane Glycoproteins, Mice, Mice, Mutant Strains, T-Lymphocytes},
	issn = {0006-4971},
	author = {Qian, J and Collins, M and Sharpe, A. H. and Hoyer, L W}
}
@article {542841,
	title = {The role of B7 costimulation in CD4/CD8 T cell homeostasis.},
	journal = {J Immunol},
	volume = {164},
	number = {7},
	year = {2000},
	month = {2000 Apr 1},
	pages = {3543-53},
	abstract = {The effect of B7-mediated costimulation on T cell homeostasis was examined in studies of B7-1 (CD80) and B7-2 (CD86) transgenic as well as B7-deficient mice. B7 overexpression in transgenic mice resulted in marked polyclonal peripheral T cell hyperplasia accompanied by skewing toward an increased proportion of CD8 single-positive cells and a decreased proportion of CD4 single-positive cells in thymus and more markedly in peripheral T cells. B7-induced T cell expansion was dependent on both CD28 and TCR expression. Transgenic overexpression of B7-1 or B7-2 resulted in down-regulation of cell surface CD28 on thymocytes and peripheral T cells through a mechanism mediated by intercellular interaction. Mice deficient in B7-1 and B7-2 exhibited changes that were the reciprocal of those observed in B7-overexpressing transgenics: a marked increase in the CD4/CD8 ratio in peripheral T cells and an increase in cell surface CD28 in thymus and peripheral T cells. These reciprocal effects of genetically engineered increase or decrease in B7 expression indicate that B7 costimulation plays a physiological role in the regulation of CD4+ and CD8+ T cell homeostasis.},
	keywords = {Animals, Antigens, CD, Antigens, CD28, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, CD4-CD8 Ratio, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, CTLA-4 Antigen, Down-Regulation, Homeostasis, Hyperplasia, Immunoconjugates, Lymphocyte Activation, Lymphoid Tissue, Membrane Glycoproteins, Mice, Mice, Congenic, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Mutant Strains, Mice, Transgenic, Phenotype, Receptors, Antigen, T-Cell, Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocyte Subsets},
	issn = {0022-1767},
	author = {Yu, X and Fournier, S and Allison, J P and Sharpe, A. H. and Hodes, R J}
}
@article {542791,
	title = {Absence of host B7 expression is sufficient for long-term murine vascularized heart allograft survival.},
	journal = {Transplantation},
	volume = {69},
	number = {5},
	year = {2000},
	month = {2000 Mar 15},
	pages = {904-9},
	abstract = {CD28 antagonists have been shown to promote long-term graft survival and induce donor-specific tolerance. In this study, the role of CD28/B7 costimulation and the relative importance of host versus donor B7 expression in allograft rejection was assessed in a murine abdominal vascularized heterotopic heart transplant model. Wild-type, CD28-deficient, or B7-1/B7-2-deficient C57BL/6 (B6) mice were grafted with allogeneic wild type or B7-1/B7-2-deficient hearts. The results demonstrate allogeneic heart grafts survive long-term in mCTLA4Ig-treated B6 and untreated B7-1/B7-2-deficient B6 recipients but not CD28KO B6 mice. B7-1/B7-2KO B6 recipients treated with anti-CD28 (PV-1) or recombinant human IL-2 rejected the heart transplants indicating that these mice are immunologically competent to reject grafts if costimulatory signals are supplied or bypassed. Finally, there was no difference in rejection between normal animals transplanted with wild-type versus B7-1/B7-2-deficient hearts. These results support a critical role for B7-expressing host antigen presenting cells in the rejection of heart allografts in mice and differences among B7KO and CD28KO animals.},
	keywords = {Animals, Antibodies, Monoclonal, Antigens, CD28, Antigens, CD80, Coronary Circulation, Graft Rejection, Graft Survival, Heart Transplantation, Humans, Interleukin-2, Mice, Mice, Inbred Strains, Mice, Knockout, Myocardium, Protein Isoforms, Recombinant Proteins, Skin Transplantation, Time Factors, Tissue Donors, Transplantation, Homologous},
	issn = {0041-1337},
	author = {Szot, G L and Zhou, P and Sharpe, A. H. and He, G and Kim, O and Newell, K A and Bluestone, J A and Thistlethwaite, J R}
}
@article {542796,
	title = {Functional equivalency of B7-1 and B7-2 for costimulating plasmid DNA vaccine-elicited CTL responses.},
	journal = {J Immunol},
	volume = {165},
	number = {12},
	year = {2000},
	month = {2000 Dec 15},
	pages = {6791-5},
	abstract = {A costimulatory signal in addition to an Ag-specific stimulus is required for optimal activation of T lymphocytes. CD28, the primary positive costimulatory receptor on T cells, has two identified ligands, B7-1 and B7-2. Whether B7-1 and B7-2 have identical, overlapping, or distinct functions remains unresolved. In this study, we show that mice lacking B7-2 were unable to generate CTL responses following immunization with a plasmid DNA vaccine. The ability of these B7-2-deficient mice to generate CTL responses following plasmid gp120 DNA vaccination was fully reconstituted by coadministering either a plasmid expressing B7-2 or B7-1. Moreover, the ability to generate CTL responses following plasmid DNA vaccination in mice lacking both B7-1 and B7-2 could be reconstituted by administering either plasmid B7-1 or plasmid B7-2 with the vaccine construct. These data demonstrate that either B7-1 or B7-2 administered concurrently with a plasmid DNA vaccine can fully costimulate vaccine-elicited CTL responses. Functional differences between B7-1 and B7-2 observed in vivo therefore may not reflect inherent differences in the interactions of CD28 with these ligands.},
	keywords = {Adjuvants, Immunologic, AIDS Vaccines, Amino Acid Sequence, Animals, Antigens, CD, Antigens, CD80, Antigens, CD86, Cytotoxicity, Immunologic, Dose-Response Relationship, Immunologic, Epitopes, T-Lymphocyte, HIV Envelope Protein gp120, HIV-1, Injections, Intramuscular, Kinetics, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Knockout, Molecular Sequence Data, Plasmids, T-Lymphocytes, Cytotoxic, Vaccines, DNA},
	issn = {0022-1767},
	author = {Santra, S and Barouch, D H and Jackson, S S and Kuroda, M J and Schmitz, J E and Lifton, M A and Sharpe, A. H. and Letvin, N L}
}
@article {542801,
	title = {Intercellular adhesion molecule 1 is critical for activation of CD28-deficient T cells.},
	journal = {J Immunol},
	volume = {165},
	number = {11},
	year = {2000},
	month = {2000 Dec 1},
	pages = {6091-8},
	abstract = {Presentation of Ag to T lymphocytes in the absence of the requisite costimulatory signals leads to an Ag-specific unresponsiveness termed anergy, whereas Ag presentation in conjunction with costimulation leads to clonal expansion. B7/CD28 signaling has been shown to provide this critical costimulatory signal and blockade of this pathway may inhibit in vitro and in vivo immune responses. Although T cells from CD28-deficient mice are lacking in a variety of responses, they nonetheless are capable of various primary and secondary responses without the induction of anergy expected in the absence of costimulation. This suggests that there may be alternative costimulatory pathways that can replace CD28 signaling under certain circumstances. In this paper, we show that ICAM-1becomes a dominant costimulatory molecule for CD28-deficient T cells. ICAM-1 costimulates anti-CD3-mediated T cell proliferation and IL-2 secretion in CD28-deficient murine T cells. Furthermore, splenocytes from ICAM-1-deficient mice could not activate CD28-deficient T cells and splenocytes lacking both ICAM and CD28 fail to proliferate in response to anti-CD3-induced T cell signals. This confirms that not only can ICAM-1 act as a CD28-independent costimulator, but it is the dominant, requisite costimulatory molecule for the activation of T cells in the absence of B7/CD28 costimulation.},
	keywords = {Amino Acid Sequence, Animals, Antigens, CD, Antigens, CD28, Antigens, CD3, Antigens, CD80, Antigens, CD86, Cercopithecus aethiops, CHO Cells, COS Cells, Cricetinae, Immune Sera, Intercellular Adhesion Molecule-1, Interleukin-2, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Data, Receptors, IgG, T-Lymphocyte Subsets, Transfection},
	issn = {0022-1767},
	author = {Gaglia, J L and Greenfield, E A and Mattoo, A and Sharpe, A. H. and Freeman, G. J. and Kuchroo, V K}
}
@article {542806,
	title = {Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4+ T cells.},
	journal = {J Immunol},
	volume = {165},
	number = {9},
	year = {2000},
	month = {2000 Nov 1},
	pages = {5035-40},
	abstract = {The inducible costimulatory (ICOS) molecule is expressed by activated T cells and has homology to CD28 and CD152. ICOS binds B7h, a molecule expressed by APC with homology to CD80 and CD86. To investigate regulation of ICOS expression and its role in Th responses we developed anti-mouse ICOS mAbs and ICOS-Ig fusion protein. Little ICOS is expressed by freshly isolated mouse T cells, but ICOS is rapidly up-regulated on most CD4(+) and CD8(+) T cells following stimulation of the TCR. Strikingly, ICOS up-regulation is significantly reduced in the absence of CD80 and CD86 and can be restored by CD28 stimulation, suggesting that CD28-CD80/CD86 interactions may optimize ICOS expression. Interestingly, TCR-transgenic T cells differentiated into Th2 expressed significantly more ICOS than cells differentiated into Th1. We used two methods to investigate the role of ICOS in activation of CD4(+) T cells. First, CD4(+) cells were stimulated with beads coated with anti-CD3 and either B7h-Ig fusion protein or control Ig fusion protein. ICOS stimulation enhanced proliferation of CD4(+) cells and production of IFN-gamma, IL-4, and IL-10, but not IL-2. Second, TCR-transgenic CD4(+) T cells were stimulated with peptide and APC in the presence of ICOS-Ig or control Ig. When the ICOS:B7h interaction was blocked by ICOS-Ig, CD4(+) T cells produced more IFN-gamma and less IL-4 and IL-10 than CD4(+) cells differentiated with control Ig. These results demonstrate that ICOS stimulation is important in T cell activation and that ICOS may have a particularly important role in development of Th2 cells.},
	keywords = {Adjuvants, Immunologic, Animals, Antigens, CD28, Antigens, Differentiation, T-Lymphocyte, Binding, Competitive, CD4-Positive T-Lymphocytes, Cell Differentiation, Cytokines, Immunoglobulins, Inducible T-Cell Co-Stimulator Ligand, Inducible T-Cell Co-Stimulator Protein, Ligands, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Transgenic, Proteins, Recombinant Fusion Proteins, Th1 Cells, Th2 Cells, Up-Regulation},
	issn = {0022-1767},
	author = {McAdam, A J and Chang, T T and Lumelsky, A E and Greenfield, E A and Boussiotis, V. A. and Duke-Cohan, J S and Chernova, T and Malenkovich, N and Jabs, C and Kuchroo, V K and Ling, V and Collins, M and Sharpe, A. H. and Freeman, G. J.}
}
@article {542961,
	title = {B7-1 or B7-2 is required to produce the lymphoproliferative phenotype in mice lacking cytotoxic T lymphocyte-associated antigen 4 (CTLA-4).},
	journal = {J Exp Med},
	volume = {189},
	number = {2},
	year = {1999},
	month = {1999 Jan 18},
	pages = {435-40},
	abstract = {The costimulatory molecules B7-1 and B7-2 regulate T lymphocyte activation by delivering activating signals through CD28 and inhibitory signals through cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). The importance of CTLA-4-mediated inhibition was demonstrated by the uncontrolled T cell activation and lymphoproliferative disease that develops in CTLA-4-deficient (-/-) mice. To examine the role of B7 signaling in the activation of CTLA-4-deficient T cells, we bred CTLA-4(-/-) mice with mice lacking B7-1, B7-2, or both B7 molecules. The CTLA-4/B7-1(-/-) and the CTLA-4/B7-2(-/-) mice develop lymphoproliferation and enhanced T cell activation. Mice lacking CTLA-4, B7-1, and B7-2 have a normal life-span, and do not have lymphocytic infiltrates in any organs, or increased T cell activation. Therefore, the two B7 molecules have overlapping functions, since either B7-1 or B7-2 alone can cause the CTLA-4(-/-) phenotype. Elimination of both B7-1 and B7-2 from the CTLA-4- deficient mouse abrogates the lymphocyte activation and disease, and does not reveal evidence for additional stimulatory CD28 ligands. The CTLA-4(-/-) phenotype can be reproduced with anti-CD28 antibody in mice lacking CTLA-4, B7-1, and B7-2, but wild-type mice are unaffected by the same treatment. This suggests that the inhibitory function of CTLA-4 can overcome strong CD28-mediated signaling in vivo.},
	keywords = {Animals, Antibodies, Antigens, CD, Antigens, CD28, Antigens, CD3, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, Cell Division, CTLA-4 Antigen, Disease Models, Animal, Flow Cytometry, Immunoconjugates, Lymphoproliferative Disorders, Membrane Glycoproteins, Mice, Mice, Knockout, Phenotype, T-Lymphocytes, Cytotoxic},
	issn = {0022-1007},
	author = {Mandelbrot, D A and McAdam, A J and Sharpe, A. H.}
}
@article {542911,
	title = {B7 costimulation in the development of lupus: autoimmunity arises either in the absence of B7.1/B7.2 or in the presence of anti-b7.1/B7.2 blocking antibodies.},
	journal = {J Immunol},
	volume = {163},
	number = {4},
	year = {1999},
	month = {1999 Aug 15},
	pages = {2322-9},
	abstract = {Costimulatory molecules, termed B7.1 and B7.2, are present on the surfaces of APC and are important for the activation of T lymphocytes specific for both foreign Ags and autoantigens. We have examined the role of B7 costimulation in the MRL-lpr/lpr murine model of human systemic lupus erythematosus. MRL-lpr/lpr mice receiving both anti-B7.1 and anti-B7.2 Abs expressed significantly lower anti-small nuclear ribonucleoprotein particles (snRNP) and anti-dsDNA autoantibodies than did untreated mice. Anti-B7.2 Ab treatment alone inhibited anti-dsDNA autoantibody expression while having no effect on anti-snRNP autoantibody expression. Anti-B7.1 Ab treatment alone did not change the expression of either anti-snRNP or anti-dsDNA autoantibodies. Parallel studies performed in MRL-lpr/lpr mice genetically deficient in either B7.1 or B7.2 expressed autoantibody profiles comparable to those found in wild-type MRL-lpr/lpr mice. However, B7.1-deficient MRL-lpr/lpr mice exhibited distinct and more severe glomerulonephritis while B7.2-deficient MRL-lpr/lpr mice had significantly milder or absent kidney pathology as compared with age-matched wild-type mice. These studies indicate that each B7 costimulatory signal may control unique pathological events in murine systemic lupus erythematosus that may not always be apparent in autoantibody titers alone.},
	keywords = {Animals, Antibodies, Antinuclear, Antibodies, Blocking, Antibodies, Monoclonal, Antigens, CD, Antigens, CD80, Antigens, CD86, Autoantibodies, DNA, Glomerulonephritis, Kidney, Lupus Erythematosus, Systemic, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred MRL lpr, Mice, Knockout, Ribonucleoproteins, Small Nuclear},
	issn = {0022-1767},
	author = {Liang, B and Gee, R J and Kashgarian, M J and Sharpe, A. H. and Mamula, M J}
}
@article {542941,
	title = {B7-2 is required for the progression but not the initiation of the type 2 immune response to a gastrointestinal nematode parasite.},
	journal = {J Immunol},
	volume = {162},
	number = {7},
	year = {1999},
	month = {1999 Apr 1},
	pages = {4133-9},
	abstract = {T cells require CD28/CTLA-4 costimulatory molecule interactions in addition to Ag-specific signals through the TCR for in vivo effector Th cell function. Some studies have suggested that the ligands for these costimulatory molecules may differentially influence effector T cell function with B7-2 favoring a type 2 response and B7-1 favoring a type 1 response, while other studies have suggested that these molecules may be redundant. The recent development of B7-2-deficient mice permits the direct analysis of the requirement of B7-2 during a type 2 immune response to an infectious pathogen. We have examined, in B7-2-deficient mice, effector Th cell function and the associated type 2 immune response following infection with Heligmosomoides polygyrus, a natural murine parasitic nematode. Elevations in cytokine gene expression and protein secretion were pronounced and comparable in inoculated B7-2-/- and B7-2+/+ mice at day 8 after H. polygyrus inoculation. However, by day 14 after infection, increases in T cell cytokine expression were markedly inhibited in H. polygyrus-inoculated B7-2-/- mice. Furthermore, elevations in serum IgE and germinal center formation were inhibited at later stages of the immune response, while elevations in serum IgG1 persisted. These findings suggest that certain T-dependent components vary in their B7-2-dependency during the type 2 immune response. They further demonstrate that B7-2 interactions are not necessary for the initiation of the type 2 immune response, but are instead required for its progression after the development of effector T cells.},
	keywords = {Animals, Antigens, CD, Antigens, CD86, Cytokines, Digestive System, Fertility, Germinal Center, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Knockout, Nematospiroides dubius, Strongylida Infections, Th2 Cells},
	issn = {0022-1767},
	author = {Greenwald, R J and Urban, J F and Ekkens, M J and Chen, S. and Nguyen, D and Fang, H and Finkelman, F D and Sharpe, A. H. and Gause, W C}
}
@article {542956,
	title = {CD48-deficient mice have a pronounced defect in CD4(+) T cell activation.},
	journal = {Proc Natl Acad Sci U S A},
	volume = {96},
	number = {3},
	year = {1999},
	month = {1999 Feb 2},
	pages = {1019-23},
	abstract = {We have generated mice deficient in the expression of the lymphocyte cell surface antigen CD48 (Blast-1, BCM1, sgp-60) by gene targeting in embryonic stem cells. Mice homozygous for the CD48 mutation (CD48(-/-) mice) are severely impaired in CD4(+) T cell activation. Proliferative responses to mitogens, anti-CD3 mAb, and alloantigen are all reduced. Experiments in which T cells and antigen-presenting cells from either wild-type or CD48(-/-) mice were cocultured reveal that CD48 is important on both T cells and antigen-presenting cells. The most dramatic impairment was observed in experiments in which highly purified T cells were stimulated through the T cell receptor in the presence of the phorbol ester, phorbol 12-myristate 13-acetate. The results of these experiments raise the possibility that CD48 plays a role in signaling through the T cell receptor.},
	keywords = {Animals, Antibodies, Monoclonal, Antigens, CD, Antigens, CD3, CD4-Positive T-Lymphocytes, Cells, Cultured, Homozygote, Lymph Nodes, Lymphocyte Activation, Lymphoid Tissue, Mice, Mice, Knockout, Spleen, Stem Cells, Thymus Gland},
	issn = {0027-8424},
	author = {Gonz{\'a}lez-Cabrero, J and Wise, C J and Latchman, Y and Freeman, G. J. and Sharpe, A. H. and Reiser, H}
}
@article {542921,
	title = {CTLA-4 and T cell activation.},
	journal = {Curr Opin Immunol},
	volume = {11},
	number = {3},
	year = {1999},
	month = {1999 Jun},
	pages = {294-300},
	abstract = {The past year has seen significant advances in our understanding of the role of cytotoxic T lymphocyte antigen 4 (CTLA-4) in regulating T cell activation and tolerance. Recent studies indicate that CTLA-4 not only counterbalances CD28 signals but also can inhibit T cell responses independently of CD28. Recent work has also revealed a role for CTLA-4 in regulating Th1/Th2 differentiation. Manipulation of CTLA-4 in animal models of autoimmunity has shown that CTLA-4 regulates both the initiation and the progression of autoimmune diseases.},
	keywords = {Animals, Antigens, CD, Antigens, CD28, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, Apoptosis, Autoimmunity, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Differentiation, Cell Division, CTLA-4 Antigen, Humans, Immune Tolerance, Immunoconjugates, Ligands, Lymphocyte Activation, Membrane Glycoproteins, Receptors, Immunologic, Signal Transduction, T-Lymphocytes, Thymus Gland},
	issn = {0952-7915},
	author = {Oosterwegel, M A and Greenwald, R J and Mandelbrot, D A and Lorsbach, R B and Sharpe, A. H.}
}
@article {542946,
	title = {Experimental murine schistosomiasis in the absence of B7 costimulatory molecules: reversal of elicited T cell cytokine profile and partial inhibition of egg granuloma formation.},
	journal = {J Immunol},
	volume = {162},
	number = {5},
	year = {1999},
	month = {1999 Mar 1},
	pages = {2884-9},
	abstract = {The granulomatous inflammation in infection with the helminth Schistosoma mansoni represents a cellular hypersensitivity reaction mediated by, and dependent upon, MHC class II-restricted CD4+ Th cells sensitized to parasite egg Ags. The current work examines the role and significance of the B7:CD28/CTLA-4 pathway in providing the costimulation necessary for the activation of these pathogenic T cells. In vitro T cell responses in B7-1-/- mice, 7-8 wk postinfection, were no different from wild-type controls, but the absence of B7-2 molecules resulted in a decrease in egg Ag-induced proliferation with increased IFN-gamma production. Both B7-1-/- and B7-2-/- mice exhibited intact granuloma formation. In contrast, CD4+ Th cells from B7-1/2 double-deficient mice displayed a dramatic loss of proliferative capacity upon stimulation with egg Ag. Most strikingly, these T cells secreted only IFN-gamma, but not IL-4 and IL-10, a pattern entirely opposite to that displayed by wild-type controls. Despite these major differences in T cell reactivity, B7-1/2-/- mice had only a limited reduction of granuloma size and fibrosis, without appreciable difference in cellular composition. These results show that substantial granuloma formation can occur under conditions of limited T cell expansion and restricted Th1-type cytokine production. They also support the notion that the combined effect of B7 signaling is not as critical for Th1 cell activation as it is for the development of the Th2 dominant environment characteristic of the evolving schistosome infection in H-2b mice.},
	keywords = {Animals, Antigens, CD, Antigens, CD28, Antigens, CD80, Antigens, Differentiation, CTLA-4 Antigen, Cytokines, Granuloma, Immunoconjugates, Liver, Lymphocyte Activation, Mice, Ovum, Schistosomiasis mansoni, T-Lymphocytes, Th2 Cells},
	issn = {0022-1767},
	author = {Hernandez, H J and Sharpe, A. H. and Stadecker, M J}
}
@article {542936,
	title = {Host B7-1 and B7-2 costimulatory molecules contribute to the eradication of B7-1-transfected P815 tumor cells via a CD8+ T cell-dependent mechanism.},
	journal = {J Immunol},
	volume = {162},
	number = {8},
	year = {1999},
	month = {1999 Apr 15},
	pages = {4817-23},
	abstract = {B7-1 (CD80)-transfected P815 tumor cells were previously shown to elicit tumor-eradicating immunity that leads to the regression of B7-1+ P815 tumors after transient growth in normal syngeneic (DBA/2) mice. Here, we show that not only the B7-1 molecule but also the B7-2 (CD86) molecule contributed to the eradication of B7-1+ P815 tumors. The B7-1 molecule that contributed to the eradication of B7-1+ P815 tumors was expressed not only on the tumor cells but also on host APCs, including MAC-1+ cells. The B7-2 molecule that contributed to the eradication of B7-1+ P815 tumors was expressed only on host APCs, such as B220+ cells, and not on the tumor cells. In spite of the fact that B7-expressing host APCs contributed to the eradication of B7-1+ P815 tumors, only CD8+ T cells without help from CD4+ T cells were important for tumor eradication. Taken together, these findings indicate that in addition to the ability of B7-1-transfected tumor cells to stimulate CD8+ T cell-mediated tumor-eradicating immunity directly, such tumor cells can also stimulate CD8+ T cell-mediated tumor-eradicating immunity indirectly as a result of cross-priming through B7-expressing host APCs.},
	keywords = {Animals, Antigen-Presenting Cells, Antigens, CD, Antigens, CD80, Antigens, CD86, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Female, Lymph Nodes, Mast-Cell Sarcoma, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Inbred DBA, Mice, Knockout, Neoplasm Transplantation, Transfection, Tumor Cells, Cultured, Up-Regulation},
	issn = {0022-1767},
	author = {La Motte, R N and Sharpe, A. H. and Bluestone, J A and Mokyr, M B}
}
@article {542931,
	title = {Lymphoproliferative disorder in CTLA-4 knockout mice is characterized by CD28-regulated activation of Th2 responses.},
	journal = {J Immunol},
	volume = {162},
	number = {10},
	year = {1999},
	month = {1999 May 15},
	pages = {5784-91},
	abstract = {Mice lacking CTLA-4 die at an age of 2-3 wk due to massive lymphoproliferation, leading to lymphocytic infiltration and destruction of major organs. The onset of the lymphoproliferative disease can be delayed by treatment with murine CTLA4Ig (mCTLA4Ig), starting day 12 after birth. In this study, we have characterized the T cells present in CTLA-4-deficient mice before and after mCTLA4Ig treatment. The T cells present in CTLA-4-deficient mice express the activation markers, CD69 and IL-2R; down-regulate the lymphoid homing receptor, CD62L; proliferate spontaneously in vitro and cannot be costimulated with anti-CD28 mAb consistent with a hyperactivated state. The T cells from CTLA-4-deficient mice survive longer in culture correlating with higher expression of the survival factor, Bcl-xL, in these cells. Most significantly, the CD4+ T cell subset present in CTLA-4-deficient mice secretes high levels of IL-4 and IL-5 upon TCR activation. Treatment of CTLA-4-deficient mice treated with mCTLA4Ig reverses the activation and hyperproliferative phenotype of the CTLA-4-deficient T cells and restores the costimulatory activity of anti-CD28 mAb. Furthermore, T cells from mCTLA4Ig-treated mice are not skewed toward a Th2 cytokine phenotype. Thus, CTLA-4 regulates CD28-dependent peripheral activation of CD4+ T cells. This process results in apoptosis-resistant, CD4+ T cells with a predominantly Th2 phenotype that may be involved in the lethal phenotype in these animals.},
	keywords = {Animals, Antibodies, Monoclonal, Antigens, CD, Antigens, CD28, Antigens, Differentiation, bcl-X Protein, CD4-Positive T-Lymphocytes, CTLA-4 Antigen, Immune Tolerance, Immunoconjugates, Immunosuppressive Agents, Interferon-gamma, Interleukin-2, Lymphocyte Activation, Lymphoproliferative Disorders, Mice, Mice, Knockout, Proto-Oncogene Proteins c-bcl-2, T-Lymphocyte Subsets, T-Lymphocytes, Th2 Cells},
	issn = {0022-1767},
	author = {Khattri, R and Auger, J A and Griffin, M D and Sharpe, A. H. and Bluestone, J A}
}
@article {542916,
	title = {Neural stem cells as engraftable packaging lines can mediate gene delivery to microglia: evidence from studying retroviral env-related neurodegeneration.},
	journal = {J Virol},
	volume = {73},
	number = {8},
	year = {1999},
	month = {1999 Aug},
	pages = {6841-51},
	abstract = {The induction of spongiform myeloencephalopathy by murine leukemia viruses is mediated primarily by infection of central nervous system (CNS) microglia. In this regard, we have previously shown that CasBrE-induced disease requires late, rather than early, virus replication events in microglial cells (W. P. Lynch et al., J. Virol. 70:8896-8907, 1996). Furthermore, neurodegeneration requires the presence of unique sequences within the viral env gene. Thus, the neurodegeneration-inducing events could result from microglial expression of retroviral envelope protein alone or from the interaction of envelope protein with other viral structural proteins in the virus assembly and maturation process. To distinguish between these possible mechanisms of disease induction, we engineered the engraftable neural stem cell line C17-2 into packaging/producer cells in order to deliver the neurovirulent CasBrE env gene to endogenous CNS cells. This strategy resulted in significant CasBrE env expression within CNS microglia without the appearance of replication competent virus. CasBrE envelope expression within microglia was accompanied by increased expression of activation markers F4/80 and Mac-1 (CD11b) but failed to induce spongiform neurodegenerative changes. These results suggest that envelope expression alone within microglia is not sufficient to induce neurodegeneration. Rather, microglia-mediated disease appears to require neurovirulent Env protein interaction with other viral proteins during assembly or maturation. More broadly, the results presented here prove the efficacy of a novel method by which neural stem cell biology may be harnessed for genetically manipulating the CNS, not only for studying neurodegeneration but also as a paradigm for the disseminated distribution of retroviral vector-transduced genes.},
	keywords = {Animals, Cell Line, Gene Transfer Techniques, Genes, env, Hematopoietic Stem Cell Transplantation, Mice, Microglia, Nerve Degeneration, Retroviridae, Retroviridae Infections, Stem Cells},
	issn = {0022-538X},
	author = {Lynch, W P and Sharpe, A. H. and Snyder, E Y}
}
@article {542926,
	title = {Opposing roles of CD28:B7 and CTLA-4:B7 pathways in regulating in vivo alloresponses in murine recipients of MHC disparate T cells.},
	journal = {J Immunol},
	volume = {162},
	number = {11},
	year = {1999},
	month = {1999 Jun 1},
	pages = {6368-77},
	abstract = {Blockade with B7 antagonists interferes with CD28:B7 and CTLA-4:B7 interactions, which may have opposing effects. We have examined the roles of CD28:B7 and CTLA-4:B7 on in vivo alloresponses. A critical role of B7:CD28 was demonstrated by markedly compromised expansion of CD28-deficient T cells and diminished graft-versus-host disease lethality of limited numbers of purified CD4+ or CD8+ T cells. When high numbers of T cells were infused, the requirement for CD28:B7 interaction was lessened. In lethally irradiated recipients, anti-CTLA-4 mAb enhanced in vivo donor T cell expansion, but did not affect, on a per cell basis, anti-host proliferative or CTL responses of donor T cells. Graft-versus-host lethality was accelerated by anti-CTLA-4 mAb infusion given early post-bone marrow transplantation (BMT), mostly in a CD28-dependent fashion. Donor T cells obtained from anti-CTLA-4 mAb-treated recipients were skewed toward a Th2 phenotype. Enhanced T cell expansion in mAb-treated recipients was strikingly advantageous in the graft-versus-leukemia effects of delayed donor lymphocyte infusion. In two different systems, anti-CTLA-4 mAb enhanced the rejection of allogeneic T cell-depleted marrow infused into sublethally irradiated recipients. We conclude that blockade of the selective CD28-B7 interactions early post-BMT, which preserve CTLA-4:B7 interactions, would be preferable to blocking both pathways. For later post-BMT, the selective blockade of CTLA-4:B7 interactions provides a potent and previously unidentified means for augmenting the GVL effect of delayed donor lymphocyte infusion.},
	keywords = {Animals, Antibodies, Blocking, Antibodies, Monoclonal, Antigens, CD, Antigens, CD28, Antigens, CD80, Antigens, Differentiation, Bone Marrow Transplantation, CTLA-4 Antigen, Graft Rejection, Graft vs Host Disease, Graft vs Tumor Effect, Histocompatibility Antigens, Immunoconjugates, Lymphocyte Transfusion, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, SCID, Postoperative Period, Signal Transduction, Spleen, T-Lymphocytes},
	issn = {0022-1767},
	author = {Blazar, B R and Taylor, P A and Panoskaltsis-Mortari, A and Sharpe, A. H. and Vallera, D A}
}
@article {542951,
	title = {The role of CD80, CD86, and CTLA4 in alloimmune responses and the induction of long-term allograft survival.},
	journal = {J Immunol},
	volume = {162},
	number = {4},
	year = {1999},
	month = {1999 Feb 15},
	pages = {1947-51},
	abstract = {Blocking the interaction of the CD28 costimulatory receptor with its ligands, CD80 and CD86, inhibits in vivo immune responses, such as allograft rejection, and in some instances induces tolerance. Previously, we found that CTLA4Ig, which blocks the CD28/CTLA-4 (CD152) ligands CD80 and CD86, can be used to induce transplantation tolerance to vascularized allografts. Recent data suggest that an intact CD152-negative signaling pathway is essential for induction of tolerance to nominal Ags. Here, we show that blockade of CD152 using an anti-CD152 mAb at the time of transplantation prevents the induction of long-term allograft survival by agents that target CD80 and CD86. In contrast, CD152 signals are not required for the maintenance of established graft survival. We also report for the first time that blockade of CD86 alone can induce long-term graft survival. This requires that anti-CD86 mAb is given on the day of transplantation and also depends upon an intact CD152 pathway. This result, plus experiments using CD80-deficient mice, suggests a dominant role for CD80 molecules on donor cells as the relevant ligand for CD152. We additionally find that blockade of CD152 at the time of transplantation does not interfere with the effectiveness of anti-CD154 mAbs, suggesting distinct mechanisms for inhibition of graft rejection by blocking the CD28 vs CD154 pathways.},
	keywords = {Animals, Antibodies, Blocking, Antibodies, Monoclonal, Antigens, CD, Antigens, CD40, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, CD40 Ligand, CTLA-4 Antigen, Graft Survival, Heart Transplantation, Immunoconjugates, Ligands, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred Strains, Mice, Knockout, Time Factors, Transplantation, Homologous},
	issn = {0022-1767},
	author = {Judge, T A and Z. Wu and Zheng, X G and Sharpe, A. H. and Sayegh, M H and Turka, L A}
}
@article {542876,
	title = {Cognate stimulatory B-cell-T-cell interactions are critical for T-cell help recruited by glycoconjugate vaccines.},
	journal = {Infect Immun},
	volume = {67},
	number = {12},
	year = {1999},
	month = {1999 Dec},
	pages = {6375-84},
	abstract = {Covalent linkage of a bacterial polysaccharide to an immunogenic protein greatly enhances the carbohydrate{\textquoteright}s immunogenicity and induces polysaccharide-specific B-cell memory in vivo. These findings have spurred the development of glycoconjugate vaccines for serious bacterial infections. The specific B-cell-T-cell interactions responsible for recruitment of T-cell help by glycoconjugate vaccines are not well defined. We used mice deficient in molecules critical for stimulatory, cognate B-cell-T-cell interactions to study how T cells improve the immunogenicity of a glycoconjugate vaccine against group B streptococcal disease. Isotype switching to immunoglobulin G (IgG) was abrogated in mice deficient in major histocompatibility complex (MHC) class II antigen (Ag)-T-cell receptor (TCR), B7-CD28, or CD40-CD40L interactions. However, expression of either the B7-1 or the B7-2 molecule on antigen-presenting cells was sufficient for optimal T-cell costimulation. T cells activated by the vaccine also played a pivotal role in determining the magnitude of the IgM response to the polysaccharide. Comparable results were obtained with pathway antagonists. These data suggest that MHC class II Ag-TCR, B7-CD28, and CD40-CD40L interactions are critical for immune responses to glycoconjugate vaccines in vivo.},
	keywords = {Animals, Antibodies, Bacterial, Antigens, CD, Antigens, CD40, Antigens, CD80, Antigens, CD86, B-Lymphocytes, Bacterial Vaccines, CD40 Ligand, Histocompatibility Antigens Class II, Immunoglobulin G, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Nude, Mice, Transgenic, Polysaccharides, Bacterial, Streptococcus agalactiae, T-Lymphocytes, Vaccination, Vaccines, Conjugate},
	issn = {0019-9567},
	author = {Guttormsen, H K and Sharpe, A. H. and Chandraker, A K and Brigtsen, A K and Sayegh, M H and Kasper, D L}
}
@article {542886,
	title = {Complete sequence determination of the mouse and human CTLA4 gene loci: cross-species DNA sequence similarity beyond exon borders.},
	journal = {Genomics},
	volume = {60},
	number = {3},
	year = {1999},
	month = {1999 Sep 15},
	pages = {341-55},
	abstract = {CTLA4 (CD152), a receptor for the B7 costimulatory molecules (CD80 and CD86), is considered a fundamental regulator of T-cell activation. In this paper, we present the complete primary structure of the mouse and human CTLA4 gene loci. Sequence comparison between the mouse and the human CTLA4 gene loci revealed a high degree of sequence conservation both for homologous noncoding regions (65-78\% identity) and for coding regions (72-98\% identity), with an overall score of 71\% over the entire length of the two genes. Of the CTLA4 genomic regions aligned, five simple repetitive elements were found in the mouse locus, whereas two simple repetitive sequences were localized on the human locus. RNA blot analysis of mouse and human primary tissues indicated that both CTLA4 and T-cell receptor transcripts were found in most organs with generally higher levels in lymphoid tissues. The conservation of CTLA4 gene patterning raises the possibility that constrained gene evolution of CTLA4 may be linked to conserved transcriptional control of this locus.},
	keywords = {Animals, Antigens, CD, Antigens, Differentiation, Base Sequence, Blotting, Northern, Cloning, Molecular, Conserved Sequence, Cross Reactions, CTLA-4 Antigen, DNA, Exons, Gene Expression Regulation, Humans, Immunoconjugates, Immunoglobulin Fc Fragments, Mice, Molecular Sequence Data, Phylogeny, Repetitive Sequences, Nucleic Acid, RNA, Sequence Analysis, Sequence Analysis, Protein, Sequence Homology, Nucleic Acid, Species Specificity, Tissue Distribution},
	issn = {0888-7543},
	doi = {10.1006/geno.1999.5930},
	author = {Ling, V and Wu, P W and Finnerty, H F and Sharpe, A. H. and Gray, G S and Collins, M}
}
@article {542891,
	title = {Expression of B7 molecules in recipient, not donor, mice determines the survival of cardiac allografts.},
	journal = {J Immunol},
	volume = {163},
	number = {7},
	year = {1999},
	month = {1999 Oct 1},
	pages = {3753-7},
	abstract = {Blockade of the CD28/CTLA4/B7 costimulatory pathway using CTLA4-Ig has great therapeutic potential, and has been shown to prolong allograft survival in a variety of animal models. To gain further insight into the mechanism by which costimulatory blockade prevents allograft rejection, we studied cardiac allograft survival in the complete absence of B7 costimulation using mice lacking B7-1 and B7-2 (B7-1/B7-2-/- mice). To determine the role of B7 on donor vs recipient cells, we used B7-1/B7-2-/- mice as either donors or recipients of allografts. Wild-type (WT) recipients acutely reject fully allogeneic hearts from both WT and B7-1/B7-2-/- mice. In contrast, B7-1/B7-2-/- recipients allow long-term survival of grafts from both WT and B7-1/B7-2-/- mice, with minimal histologic evidence of either acute or chronic rejection in grafts harvested after 90 days. The B7-1/B7-2-/- mice acutely reject B7-1/B7-2-/- allografts if CD28 stimulation is restored by the administration of Ab to CD28 and can mount an alloresponse in mixed lymphocyte reactions. Therefore, B7-1/B7-2-/- mice are capable of generating alloresponses both in vivo and in vitro. Our results demonstrate that in the alloresponse to mouse heterotopic cardiac transplantation, B7 molecules on recipient cells rather than donor cells provide the critical costimulatory signals. The indefinite survival of allografts into B7-1/B7-2-/- recipients further shows that the absence of B7 costimulation alone is sufficient to prevent rejection.},
	keywords = {Animals, Antigens, CD, Antigens, CD28, Antigens, CD80, Antigens, Differentiation, CTLA-4 Antigen, Cytokines, Graft Rejection, Graft Survival, Heart Transplantation, Immunoconjugates, Lymphocyte Activation, Lymphocyte Culture Test, Mixed, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Signal Transduction, T-Lymphocyte Subsets, Th2 Cells, Transplantation, Homologous},
	issn = {0022-1767},
	author = {Mandelbrot, D A and Furukawa, Y and McAdam, A J and Alexander, S I and Libby, P and Mitchell, R N and Sharpe, A. H.}
}
@article {542901,
	title = {Heparin is essential for the storage of specific granule proteases in mast cells.},
	journal = {Nature},
	volume = {400},
	number = {6746},
	year = {1999},
	month = {1999 Aug 19},
	pages = {769-72},
	abstract = {All mammals produce heparin, a negatively charged glycosaminoglycan that is a major constituent of the secretory granules of mast cells which are found in the peritoneal cavity and most connective tissues. Although heparin is one of the most studied molecules in the body, its physiological function has yet to be determined. Here we describe transgenic mice, generated by disrupting the N-deacetylase/N-sulphotransferase-2 gene, that cannot express fully sulphated heparin. The mast cells in the skeletal muscle that normally contain heparin lacked metachromatic granules and failed to store appreciable amounts of mouse mast-cell protease (mMCP)-4, mMCP-5 and carboxypeptidase A (mMC-CPA), even though they contained substantial amounts of mMCP-7. We developed mast cells from the bone marrow of the transgenic mice. Although these cultured cells contained high levels of various protease transcripts and had substantial amounts of mMCP-6 protein in their granules, they also failed to express mMCP-5 and mMC-CPA. Our data show that heparin controls, through a post-translational mechanism, the levels of specific cassettes of positively charged proteases inside mast cells.},
	keywords = {3T3 Cells, Amidohydrolases, Animals, Bone Marrow Cells, Carboxypeptidases, Carboxypeptidases A, Cell Differentiation, Cells, Cultured, Chymases, Coculture Techniques, Cytoplasmic Granules, Enzyme Precursors, Heparin, Intestinal Mucosa, Jejunum, Mast Cells, Mice, Mice, Transgenic, Serine Endopeptidases, Sulfates, Sulfotransferases, Trichinella spiralis, Trichinellosis, Tryptases},
	issn = {0028-0836},
	doi = {10.1038/23481},
	author = {Humphries, D.E. and Wong, G W and Friend, D S and Gurish, M F and Qiu, W T and Huang, C and Sharpe, A. H. and Stevens, R L}
}
@article {542881,
	title = {Mutual regulation between B7-1 (CD80) expressed on T cells and IL-4.},
	journal = {J Immunol},
	volume = {163},
	number = {9},
	year = {1999},
	month = {1999 Nov 1},
	pages = {4819-25},
	abstract = {We have used T cells from B7-1-deficient TCR transgenic DO11.10 mice to demonstrate a functional role for B7-1 on T cells. B7-1-deficient DO11.10 T cells produce more IL-4 than wild-type DO11.10 T cells, suggesting that B7-1 expressed by T cells regulates the differentiation of IL-4-producing cells. In addition, we found that IL-4 inhibits B7-1 expression by wild-type DO11.10 T cells. Our results suggest that there is a reciprocal relationship between B7-1 expressed on T cells and IL-4 production, which results in a modulatory feedback loop. When high levels of IL-4 are produced by T cells, B7-1 expression by T cells is inhibited, which allows amplification of IL-4 production by these T cells. When low levels of IL-4 are produced by T cells, B7-1 expression by these T cells is increased, and a further reduction in IL-4 production follows. However, in addition to being influenced by IL-4, B7-1 expression by T cells is affected by peptide concentration and by B7 costimulation from APCs. The studies presented here demonstrate that B7-1 on T cells as well as on APCs regulates IL-4 production. However, whereas B7-1 expression on APCs can promote IL-4 production, IL-4 production is inhibited by B7-1 on T cells.},
	keywords = {Amino Acid Sequence, Animals, Antigen-Presenting Cells, Antigens, CD80, CD4-Positive T-Lymphocytes, Cells, Cultured, Dose-Response Relationship, Immunologic, Epitopes, T-Lymphocyte, Interleukin-4, Interphase, Lymphocyte Activation, Lymphocyte Count, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Transgenic, Molecular Sequence Data, Ovalbumin, Peptides, STAT6 Transcription Factor, T-Lymphocytes, Trans-Activators},
	issn = {0022-1767},
	author = {Schweitzer, A N and Sharpe, A. H.}
}
@article {542861,
	title = {Ox40-ligand has a critical costimulatory role in dendritic cell:T cell interactions.},
	journal = {Immunity},
	volume = {11},
	number = {6},
	year = {1999},
	month = {1999 Dec},
	pages = {689-98},
	abstract = {The tumor necrosis factor family molecule Ox40-ligand (Ox40L) has been identified as a potential costimulatory molecule and also has been implicated in T cell homing and B cell activation. To ascertain the essential functions of Ox40L, we generated and characterized Ox40L-deficient mice. Mice lacking Ox40L exhibit an impaired contact hypersensitivity response, a dendritic cell-dependent T cell-mediated response, due to defects in T cell priming and cytokine production. In contrast, Ox40L-deficient mice do not have defects in T cell homing or humoral immune responses. In vitro, Ox40L-deficient dendritic cells are defective in costimulating T cell cytokine production. Thus, Ox40L has a critical costimulatory function in vitro and in vivo for dendritic cell:T cell interactions.},
	keywords = {3T3 Cells, Animals, Antigens, T-Independent, Dendritic Cells, Dermatitis, Contact, Haptens, Hemocyanin, Hypersensitivity, Delayed, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Ovalbumin, Receptors, Tumor Necrosis Factor, T-Lymphocytes, Tumor Necrosis Factors},
	issn = {1074-7613},
	author = {Chen, A I and McAdam, A J and Buhlmann, J E and Scott, S and Lupher, M L and Greenfield, E A and Baum, P R and Fanslow, W C and Calderhead, D M and Freeman, G. J. and Sharpe, A. H.}
}
@article {542906,
	title = {The role of CTLA-4 in regulating Th2 differentiation.},
	journal = {J Immunol},
	volume = {163},
	number = {5},
	year = {1999},
	month = {1999 Sep 1},
	pages = {2634-9},
	abstract = {To examine the role of CTLA-4 in Th cell differentiation, we used two newly generated CTLA-4-deficient (CTLA-4-/-) mouse strains: DO11. 10 CTLA-4-/- mice carrying a class II restricted transgenic TCR specific for OVA, and mice lacking CTLA-4, B7.1 and B7.2 (CTLA-4-/- B7.1/B7.2-/- ). When purified naive CD4+ DO11.10 T cells from CTLA-4-/- and wild-type mice were primed and restimulated in vitro with peptide Ag, CTLA-4-/- DO11.10 T cells developed into Th2 cells, whereas wild-type DO11.10 T cells developed into Th1 cells. Similarly, when CTLA-4-/- CD4+ T cells from mice lacking CTLA-4, B7. 1, and B7.2 were stimulated in vitro with anti-CD3 Ab and wild-type APC, these CTLA-4-/- CD4+ T cells produced IL-4 even during the primary stimulation, whereas CD4+ cells from B7.1/B7.2-/- mice did not produce IL-4. Upon secondary stimulation, CD4+ T cells from CTLA-4-/- B7.1/B7.2-/- mice secreted high levels of IL-4, whereas CD4+ T cells from B7.1/B7.2-/- mice produced IFN-gamma. In contrast to the effects on CD4+ Th differentiation, the absence of CTLA-4 resulted in only a modest effect on T cell proliferation, and increased proliferation of CTLA-4-/- CD4+ T cells was seen only during secondary stimulation in vitro. Administration of a stimulatory anti-CD28 Ab in vivo induced IL-4 production in CTLA-4-/- B7.1/B7.2-/- but not wild-type mice. These studies demonstrate that CTLA-4 is a critical and potent inhibitor of Th2 differentiation. Thus, the B7-CD28/CTLA-4 pathway plays a critical role in regulating Th2 differentiation in two ways: CD28 promotes Th2 differentiation while CTLA-4 limits Th2 differentiation.},
	keywords = {Amino Acid Sequence, Animals, Antigens, CD, Antigens, CD28, Antigens, Differentiation, CD4-Positive T-Lymphocytes, Cell Differentiation, Cell Division, CTLA-4 Antigen, Cytokines, Immune Sera, Immunoconjugates, Interleukin-4, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Inbred Strains, Mice, Transgenic, Molecular Sequence Data, Th2 Cells},
	issn = {0022-1767},
	author = {Oosterwegel, M A and Mandelbrot, D A and Boyd, S D and Lorsbach, R B and Jarrett, D Y and Abbas,A.K. and Sharpe, A. H.}
}
@article {542896,
	title = {Studies in B7-deficient mice reveal a critical role for B7 costimulation in both induction and effector phases of experimental autoimmune encephalomyelitis.},
	journal = {J Exp Med},
	volume = {190},
	number = {5},
	year = {1999},
	month = {1999 Sep 6},
	pages = {733-40},
	abstract = {The importance of B7 costimulation in regulating T cell expansion and peripheral tolerance suggests that it may also play a significant regulatory role in the development of autoimmune disease. It is unclear whether B7 costimulation is involved only in the expansion of autoreactive T cells in the periphery, or if it is also required for effector activation of autoreactive T cells in the target organ for mediating tissue injury and propagating autoimmune disease. In this study, the role of B7-CD28 costimulation and the relative importance of B7 costimulators for the induction and effector phases of experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) peptide were examined. Wild-type, B7-1/B7-2-deficient mice, or CD28-deficient C57BL/6 mice were immunized with MOG 35-55 peptide. Mice lacking both B7-1 and B7-2 or CD28 showed no or minimal clinical signs of EAE and markedly reduced inflammatory infiltrates in the brain and spinal cord. However, mice lacking either B7-1 or B7-2 alone developed clinical and pathologic EAE that was comparable to EAE in wild-type mice, indicating overlapping functions for B7-1 and B7-2. Resistance to EAE was not due to a lack of induction of T helper type 1 (Th1) cytokines, since T cells from B7-1/B7-2(-/-) mice show reduced proliferative responses, but greater interferon gamma production compared with T cells from wild-type mice. To study the role of B7 molecules in the effector phase of the disease, MOG 35-55-specific T lines were adoptively transferred into the B7-1/B7-2(-/-) and wild-type mice. Clinical and histologic EAE were markedly reduced in B7-1/B7-2(-/-) compared with wild-type recipient mice. These results demonstrate that B7 costimulation has critical roles not only in the initial activation and expansion of MOG-reactive T cells, but also in the effector phase of encephalitogenic T cell activation within the central nervous system.},
	keywords = {Adoptive Transfer, Amino Acid Sequence, Animals, Antigens, CD, Antigens, CD28, Antigens, CD80, Antigens, CD86, Encephalomyelitis, Autoimmune, Experimental, Female, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Data, Myelin Proteins, Myelin-Associated Glycoprotein, Myelin-Oligodendrocyte Glycoprotein, Peptide Fragments, T-Lymphocytes, Vaccination},
	issn = {0022-1007},
	author = {Chang, T T and Jabs, C and Sobel, R A and Kuchroo, V K and Sharpe, A. H.}
}
@article {542871,
	title = {T-cell stimulation: an abundance of B7s.},
	journal = {Nat Med},
	volume = {5},
	number = {12},
	year = {1999},
	month = {1999 Dec},
	pages = {1345-6},
	keywords = {Animals, Antigens, CD, Antigens, CD28, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, Antigens, Differentiation, T-Lymphocyte, CTLA-4 Antigen, Humans, Immunoconjugates, Inducible T-Cell Co-Stimulator Protein, Interleukin-10, Lymphocyte Activation, Membrane Glycoproteins, Mice, Signal Transduction, T-Lymphocytes},
	issn = {1078-8956},
	doi = {10.1038/70905},
	author = {Abbas,A.K. and Sharpe, A. H.}
}
@article {542851,
	title = {The B7-CD28/CTLA-4 costimulatory pathways in autoimmune disease of the central nervous system.},
	journal = {Curr Opin Immunol},
	volume = {11},
	number = {6},
	year = {1999},
	month = {1999 Dec},
	pages = {677-83},
	abstract = {The past year has seen significant advances in our understanding of the role of the B7-CD28/CTLA-4 pathway in regulating the responses of self-reactive T cells, giving impetus to manipulation of this pathway for treating human autoimmune diseases. Recent studies have demonstrated that B7-CD28 costimulation has critical roles in stimulating both the initiation and effector phases of autoimmunity and that CD28 regulates the threshold for activation of self-reactive T cells. Recent work has also revealed critical roles for CTLA-4 in limiting the extent of Th1/Th2 cell differentiation and in downregulating the responses of self-reactive T cells during both the initiation and progression of autoimmune disease.},
	keywords = {Animals, Antigens, CD, Antigens, CD28, Antigens, CD80, Antigens, Differentiation, Autoimmune Diseases, Central Nervous System Diseases, CTLA-4 Antigen, Humans, Immunoconjugates},
	issn = {0952-7915},
	author = {Anderson, D E and Sharpe, A. H. and Hafler, D A}
}
@article {542991,
	title = {The complexity of the B7-CD28/CTLA-4 costimulatory pathway.},
	journal = {Agents Actions Suppl},
	volume = {49},
	year = {1998},
	month = {1998},
	pages = {33-43},
	abstract = {There have been significant recent advances in our understanding of the role of the B7-CD28/CTLA-4 costimulatory pathway in T-cell activation and self-tolerance. Recent studies have begun to clarify how signaling through this pathway can influence cytokine production. The critical role for CTLA-4 in regulating T-cell activation and autoreactivity has been demonstrated, revealing a previously unsuspected means by which costimulation is involved in the maintenance and breakdown of self-tolerance. In vivo studies indicate the therapeutic potential of manipulating this important, but complex, immunoregulatory pathway.},
	keywords = {Animals, Antigens, CD, Antigens, CD28, Antigens, CD80, Antigens, Differentiation, CTLA-4 Antigen, Cytokines, Humans, Immunoconjugates, Lymphocyte Activation, T-Lymphocytes},
	issn = {0379-0363},
	author = {Schweitzer, A N and Sharpe, A. H.}
}
@article {542966,
	title = {Distinct roles for B7 costimulation in contact hypersensitivity and humoral immune responses to epicutaneous antigen.},
	journal = {Eur J Immunol},
	volume = {28},
	number = {12},
	year = {1998},
	month = {1998 Dec},
	pages = {4221-7},
	abstract = {Productive interactions between B7-1 and B7-2 costimulatory molecules on dendritic cells (DC) and CD28 on T cells are thought to be critical for successful antigen presentation. Epicutaneous application of haptens induces both contact hypersensitivity (CHS), an inflammatory cutaneous response mediated by CD8+ T cells, and an anti-hapten antibody response mediated by CD4+ helper T cells. The role of B7 costimulation in the immune response to oxazolone (Ox) was analyzed using mice lacking either B7-1 (B7-1-/-), B7-2 (B7-2-/-), or both (Db-/-) of these costimulatory molecules. The absence of both B7-1 and B7-2 results in diminished CHS. This inhibition is largely overcome at higher hapten sensitizing doses indicating the presence of compensatory pathways. In contrast, anti-Ox IgG1 and IgG2a responses were not detected in the absence of both B7-1 and B7-2, even at high sensitizing doses, indicating an obligatory role of B7 costimulation in IgG class switching. B7-1 and B7-2 have overlapping functions in both CHS responses and anti-hapten response. B7-2-/- mice demonstrated a modestly reduced CHS response only at very low doses of Ox (0.05\%), but responded normally at higher Ox doses, and B7-1-/- mice had CHS responses indistinguishable from those of wild-type mice. Similarly, anti-Ox IgG responses were comparable in wild-type, B7-1-/- and B7-2-/- mice. Taken together, these studies reveal distinct roles for B7 costimulation in response to epicutaneous antigens with an obligatory role for IgG class switching and an important, but nonessential role for CHS responses.},
	keywords = {Animals, Antibody Formation, Antigen Presentation, Antigens, CD, Antigens, CD80, Antigens, CD86, Dendritic Cells, Dermatitis, Contact, Membrane Glycoproteins, Mice, Mice, Knockout, Oxazolone, T-Lymphocytes},
	issn = {0014-2980},
	doi = {10.1002/(SICI)1521-4141(199812)28:12\&$\#$60;4221::AID-IMMU4221\&$\#$62;3.0.CO;2-M},
	author = {Rauschmayr-Kopp, T and Williams,I.R. and Borriello, F and Sharpe, A. H. and Kupper,T.S.}
}
@article {542971,
	title = {Importance of B7-1-expressing host antigen-presenting cells for the eradication of B7-2 transfected P815 tumor cells.},
	journal = {J Immunol},
	volume = {161},
	number = {12},
	year = {1998},
	month = {1998 Dec 15},
	pages = {6552-8},
	abstract = {We have previously shown that B7-2 (CD86)-transfected P815 tumor cells elicit tumor-eradicating immunity that leads to the regression of the B7-2+ P815 tumor after transient growth in normal DBA/2 mice. Here, we show that both the B7-2 and B7-1 (CD80) molecules contribute to the eradication of B7-2+ P815 tumors as treatment of the mice with both anti-B7-2 and anti-B7-1 mAb was required to prevent B7-2+ P815 tumor regression. The cells that expressed the B7-1 molecule following inoculation of B7-2+ P815 tumor cells into normal mice were not the tumor cells but rather host APCs including MAC-1+ cells present in the draining lymph nodes. Moreover, B7-1-expressing host APCs were found to be important for the rejection of B7-2+ P815 tumors as anti-B7-2 mAb alone, which was ineffective in preventing B7-2+ P815 tumor rejection by normal wild-type mice, was effective in preventing B7-2+ P815 tumor rejection by mice in which the B7-1 gene was disrupted. Finally, consistent with the importance of B7-1-expressing host APCs for the generation of tumor-eradicating immunity against B7-2+ P815 tumor cells, CD4+ T cells (not only CD8+ T cells) were found to participate in tumor-eradicating immunity against B7-2+ P815 tumor cells. Thus, in addition to eliciting tumor-eradicating immunity directly, B7-2+ P815 tumor cells elicit tumor-eradicating immunity indirectly through B7-1-expressing host APCs that present tumor-associated Ags to CD4+ T cells.},
	keywords = {Animals, Antigen Presentation, Antigen-Presenting Cells, Antigens, CD, Antigens, CD80, Antigens, CD86, Antigens, Neoplasm, CD4-Positive T-Lymphocytes, Cytotoxicity, Immunologic, Female, Mast-Cell Sarcoma, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Inbred DBA, Recombinant Fusion Proteins, Transfection, Tumor Cells, Cultured, Up-Regulation},
	issn = {0022-1767},
	author = {La Motte, R N and Sharpe, A. H. and Bluestone, J A and Mokyr, M B}
}
@article {542976,
	title = {The role of B7 co-stimulation in activation and differentiation of CD4+ and CD8+ T cells.},
	journal = {Immunol Rev},
	volume = {165},
	year = {1998},
	month = {1998 Oct},
	pages = {231-47},
	abstract = {The functional significance of B7 co-stimulation in T-cell activation was described first in the context of preventing the induction of anergy. The functions of this pathway are far more complex than initially appreciated in view of the existence of two B7 molecules which have specificities for both CD28 and CTLA-4, which serve to amplify and terminate T-cell responses respectively. Mice lacking B7 co-stimulators and CD28 and CTLA-4 co-stimulatory receptors are helping to clarify the functions of this key immunoregulatory pathway. In this review we will focus on the role of B7 co-stimulation in the activation and differentiation of CD4+ helper cells and CD8+ cytotoxic cells. The contribution of B7 co-stimulation to CD4+ responses depends upon the activation history of the T-cell and the strength of the T-cell antigen receptor signal. B7 co-stimulation contributes to interleukin (IL)-2 production by both naive and previously activated CD4+ T cells. B7 co-stimulation is most critical for the differentiation of naive CD4+ T cells to IL-4 producers, but predominately influences IL-2 production by previously activated CD4+ cells. B7 co-stimulation is important in development of cytotoxic T cells through both effects on T-helper cells and by direct co-stimulation of CD8+ cells.},
	keywords = {Animals, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, HLA-B7 Antigen, Humans, Leukopoiesis, Lymphocyte Activation, Mice, Signal Transduction},
	issn = {0105-2896},
	author = {McAdam, A J and Schweitzer, A N and Sharpe, A. H.}
}
@article {542981,
	title = {Studies using antigen-presenting cells lacking expression of both B7-1 (CD80) and B7-2 (CD86) show distinct requirements for B7 molecules during priming versus restimulation of Th2 but not Th1 cytokine production.},
	journal = {J Immunol},
	volume = {161},
	number = {6},
	year = {1998},
	month = {1998 Sep 15},
	pages = {2762-71},
	abstract = {The differentiation of CD4+ T cells into a Th1 vs Th2 phenotype profoundly influences the outcome of autoimmune and infectious diseases. B7 costimulation has been shown to affect the production of both Th1 and Th2 cytokines, depending on the system studied. There is, consequently, great interest in manipulating the B7 costimulatory signal for therapeutic purposes. To optimally manipulate this key immunoregulatory pathway, the contribution of B7 costimulation to cytokine production requires further clarification. We have compared the B7 requirement for cytokine production by naive vs previously activated T cells using DO11.10 TCR transgenic CD4+ T cells and splenic APCs from mice lacking B7 expression. Our data indicate that induction of IL-4 production and Th2 differentiation by naive T cells is highly dependent on B7 molecules, whereas IL-4 production by previously activated T cells is B7 independent. The predominant contribution of B7-mediated signals to Th1 cytokine production by both naive and primed T cells is upon IL-2 production (and expansion) rather than IFN-gamma (effector cytokine) production. Thus, our studies demonstrate that the antigenic experience of a T cell at the time of B7 blockade may determine whether blockade predominantly affects T cell expansion, differentiation, or effector cytokine production. These differential effects of B7 costimulation on IL-2 vs IFN-gamma production and on IL-4 production by naive vs primed T cells have important implications for understanding how B7:CD28/CTLA4 blockade can be effectively used to manipulate cytokine production in vivo.},
	keywords = {Amino Acid Sequence, Animals, Antigen-Presenting Cells, Antigens, CD, Antigens, CD80, Antigens, CD86, Cell Differentiation, Cells, Cultured, Immunization, Interleukin-2, Interleukin-4, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Inbred Strains, Mice, Knockout, Mice, Transgenic, Molecular Sequence Data, T-Lymphocyte Subsets, Th1 Cells, Th2 Cells},
	issn = {0022-1767},
	author = {Schweitzer, A N and Sharpe, A. H.}
}
@article {543021,
	title = {B7-1 and B7-2 have overlapping, critical roles in immunoglobulin class switching and germinal center formation.},
	journal = {Immunity},
	volume = {6},
	number = {3},
	year = {1997},
	month = {1997 Mar},
	pages = {303-13},
	abstract = {Humoral immune responses were characterized in mouse strains lacking either or both B7 molecules. Mice deficient in both B7-1 and B7-2 failed to generate antigen-specific IgG1 and IgG2a responses and lacked germinal centers when immunized by a number of routes and even in the presence of complete Freund{\textquoteright}s adjuvant. These results demonstrate that B7-mediated signaling plays a critical role in germinal center formation and immunoglobulin class switching in vivo. Mice lacking only B7-1 or B7-2 mounted high-titer antigen-specific IgG responses when immunized in complete Freund{\textquoteright}s adjuvant, indicating that B7-1 and B7-2 can have overlapping, compensatory functions for IgG responses. When immunized intravenously without adjuvant, B7-2-deficient mice failed to switch antibody isotypes or form germinal centers, whereas B7-1-deficient mice gave antibody responses comparable with wild-type mice. Thus, B7-2 has an important role in initiating antibody responses in the absence of adjuvant, but the induction of B7-1 by adjuvant in B7-2-deficient mice can compensate for the absence of B7-2.},
	keywords = {Adjuvants, Immunologic, Animals, Antigens, Antigens, CD, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, Antigens, T-Independent, CTLA-4 Antigen, Freund{\textquoteright}s Adjuvant, Germinal Center, Hemocyanin, Immunoconjugates, Immunoglobulin Class Switching, Immunoglobulin Fc Fragments, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout},
	issn = {1074-7613},
	author = {Borriello, F and Sethna, M P and Boyd, S D and Schweitzer, A N and Tivol, E A and Jacoby, D and Strom,T.B. and Simpson, E M and Freeman, G. J. and Sharpe, A. H.}
}
@article {543031,
	title = {B7.2 expressed by T cells does not induce CD28-mediated costimulatory activity but retains CTLA4 binding: implications for induction of antitumor immunity to T cell tumors.},
	journal = {J Immunol},
	volume = {158},
	number = {5},
	year = {1997},
	month = {1997 Mar 1},
	pages = {2025-34},
	abstract = {The B7 family of costimulatory molecules provides the second signal necessary for activation of T cells. In the absence of the second signal, responding T cells become anergic. Although predominantly expressed on professional APCs, recent evidence shows that the B7 molecules are also expressed on T cells. To study the functions of B7 molecules on T cells, we transfected murine B7.1 (CD80) and B7.2 (CD86) cDNAs into the EL4 T cell thymoma cell line and examined the transfectants for their ability to costimulate T cell proliferation in vitro and to induce antitumor immunity in vivo. Here we show that although EL4-B7.1 cells costimulate T cells and induce tumor regression, EL4-B7.2 transfectants failed to costimulate T cell proliferation or induce tumor regression. To understand the cellular basis for this difference, we examined the binding of EL4-B7.1 and EL4-B7.2 to CTLA4 and CD28. Whereas EL4-B7.1 cells bound both CTLA4-Ig and CD28-Ig, EL4-B7.2 transfectants preferentially bound CTLA4-Ig, but not CD28-Ig. Similar binding data were obtained with freshly isolated murine T cells, which have been shown to constitutively express B7.2. Our data suggest, therefore, that B7.2 expressed on T cells may not costimulate but instead inhibit the T cell response by preferential binding to CTLA4.},
	keywords = {Animals, Antigens, CD, Antigens, CD28, Antigens, CD86, Antigens, Differentiation, Cell Division, CTLA-4 Antigen, Female, Immunoconjugates, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Protein Binding, T-Lymphocytes, Thymoma, Thymus Neoplasms, Transfection, Tumor Cells, Cultured},
	issn = {0022-1767},
	author = {Greenfield, E A and Howard, E and Paradis, T and Nguyen, K and Benazzo, F and McLean, P and H{\"o}llsberg, P and Davis, G and Hafler, D A and Sharpe, A. H. and Freeman, G. J. and Kuchroo, V K}
}
@article {543026,
	title = {Embryonic lethality and impairment of haematopoiesis in mice heterozygous for an AML1-ETO fusion gene.},
	journal = {Nat Genet},
	volume = {15},
	number = {3},
	year = {1997},
	month = {1997 Mar},
	pages = {303-6},
	abstract = {Acute myeloid leukaemia (AML) is a major haematopoietic malignancy characterized by the proliferation of a malignant clone of myeloid progenitor cells. A reciprocal translocation, t(8;21)(q22;q22), observed in the leukaemic cells of approximately 40\% of patients with the M2 subtype of AML disrupts both the AML1 (CBFA2) gene on chromosome 21 and the ETO (MTG8) gene on chromosome 8 (refs 3-5). A chimaeric protein is synthesized from one of the derivative chromosomes that contains the N terminus of the AML1 transcription factor, including its DNA-binding domain, fused to most of ETO, a protein of unknown function. We generated mice that mimic human t(8;21) with a "knock-in{\textquoteright} strategy. Mice heterozygous for an AML1-ETO allele (AML1-ETO/+) die in midgestation from haemorrhaging in the central nervous system and exhibit a severe block in fetal liver haematopoiesis. This phenotype is very similar to that resulting from homozygous disruption of the AML1 (Cbfa2) or Cbfb genes, indicating that AML1-ETO blocks normal AML1 function. However, yolk sac cells from AML1-ETO/+ mice differentiated into macrophages in haematopoietic colony forming unit (CFU) assays, unlike Cbfa2-/- or Cbfb-/-cells, which form no colonies in vitro. This indicates that AML1-ETO may have other functions besides blocking wild-type AML1, a property that may be important in leukaemogenesis.},
	keywords = {Animals, Chimera, Chromosome Mapping, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Cloning, Molecular, Core Binding Factor Alpha 2 Subunit, Crosses, Genetic, DNA-Binding Proteins, Exons, Female, Fetal Death, Hematopoiesis, Heterozygote Detection, Humans, Leukemia, Myeloid, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Proto-Oncogene Proteins, Transcription Factors, Translocation, Genetic, Yolk Sac},
	issn = {1061-4036},
	doi = {10.1038/ng0397-303},
	author = {Yergeau, D A and Hetherington, C J and Wang, Q and Zhang, P and Sharpe, A. H. and Binder, M and Mar{\'\i}n-Padilla, M and Tenen, D G and Speck, N A and Zhang, D E}
}
@article {543011,
	title = {MRC OX-2 defines a novel T cell costimulatory pathway.},
	journal = {J Immunol},
	volume = {158},
	number = {10},
	year = {1997},
	month = {1997 May 15},
	pages = {4548-54},
	abstract = {T cell activation requires the engagement of the TCR as well as a second, costimulatory signal. In this study, we demonstrate that MRC OX-2 (OX-2) mediates a previously unrecognized T cell costimulatory signal leading to enhanced T cell proliferation. One extensively studied costimulatory pathway, the B7/CD28 pathway, delivers its signal when CD28 is engaged by either of two ligands, B7-1 or B7-2, expressed on APC. Recent data have suggested that an additional ligand may exist in this pathway. This possibility prompted us to search previously cloned genes with both structural and expression characteristics similar to B7-1 and B7-2. Our search yielded OX-2, a rat lymphocyte activation marker, as a promising candidate gene. We now report that Chinese hamster ovary cell transfectants expressing the OX-2 protein can costimulate murine CD4+ T cells to proliferate in an Ag-independent fashion using anti-CD3, as well as an Ag-dependent fashion using peptide. In contrast to B7-1-mediated costimulation, OX-2 does not result in detectable levels of IL-2, IL-4, or IFN-gamma. In addition, OX-2 transfectants do not bind the soluble receptor reagents of the B7/CD28 pathway (CD28-Ig and CTLA4Ig). Furthermore, OX-2 costimulation is not inhibited by CTLA4Ig, as is B7-1-mediated costimulation, but is readily inhibited with an anti-OX-2 mAb. Thus, OX-2 is a T cell costimulatory ligand that acts through a non-B7/CD28 pathway, which leads to functionally distinct consequences, as reflected by the resulting cytokine profile.},
	keywords = {Amino Acid Sequence, Animals, Antigen-Presenting Cells, Antigens, CD, Antigens, CD80, Antigens, CD86, Antigens, Surface, CHO Cells, Cloning, Molecular, Cricetinae, DNA, Complementary, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Rats, Rats, Inbred Lew, Sequence Alignment, Sequence Homology, Amino Acid, Signal Transduction, T-Lymphocytes},
	issn = {0022-1767},
	author = {Borriello, F and Lederer, J and Scott, S and Sharpe, A. H.}
}
@article {543016,
	title = {Role of costimulators in T cell differentiation: studies using antigen-presenting cells lacking expression of CD80 or CD86.},
	journal = {J Immunol},
	volume = {158},
	number = {6},
	year = {1997},
	month = {1997 Mar 15},
	pages = {2713-22},
	abstract = {For T cells to be optimally activated, recognition of Ag/MHC complexes by the TCR must be accompanied by a second, costimulatory signal that can be provided efficiently by the related costimulatory molecules CD80 (B7-1) and CD86 (B7-2). Recently, CD80 and CD86 have been implicated as differential determinants of Th1- vs Th2-type cytokine profiles. However, this remains a controversial issue since conflicting results have been obtained in different experimental models both in vivo and in vitro. To investigate the role of CD80 and CD86 in Th subset differentiation, we have examined the cytokine profiles induced in TCR transgenic T cells stimulated by peptide in association with splenic APCs obtained from knockout mice that selectively lack expression of either the CD80 or the CD86 molecule. Our data suggest that CD86, and to a lesser extent CD80, can make significant contributions to the production of both IL-4 and IFN-gamma. However, neither molecule plays an obligatory role in priming for the production of either effector cytokine. Furthermore, CD80 and CD86 contribute to the magnitude of T cell activation, but do not appear to selectively regulate Th1 vs Th2 differentiation.},
	keywords = {Amino Acid Sequence, Animals, Antibodies, Blocking, Antibodies, Monoclonal, Antigen-Presenting Cells, Antigens, CD, Antigens, CD80, Antigens, CD86, Cell Differentiation, Cells, Cultured, Cytokines, Immunization, Secondary, Interleukin-4, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Transgenic, Molecular Sequence Data, Receptors, Antigen, T-Cell, T-Lymphocytes, Th1 Cells, Th2 Cells},
	issn = {0022-1767},
	author = {Schweitzer, A N and Borriello, F and Wong, R C and Abbas,A.K. and Sharpe, A. H.}
}
@article {542996,
	title = {The costimulatory genes Cd80 and Cd86 are linked on mouse chromosome 16 and human chromosome 3.},
	journal = {Mamm Genome},
	volume = {8},
	number = {8},
	year = {1997},
	month = {1997 Aug},
	pages = {581-2},
	keywords = {Animals, Antigens, CD, Antigens, CD80, Antigens, CD86, Chromosome Mapping, Chromosomes, Artificial, Yeast, Chromosomes, Human, Pair 3, DNA Primers, Genetic Linkage, Genetic Markers, Humans, In Situ Hybridization, Fluorescence, Membrane Glycoproteins, Mice, Polymerase Chain Reaction},
	issn = {0938-8990},
	author = {Reeves, R H and Patch, D and Sharpe, A. H. and Borriello, F and Freeman, G. J. and Edelhoff, S and Disteche, C}
}
@article {543006,
	title = {CTLA4Ig prevents lymphoproliferation and fatal multiorgan tissue destruction in CTLA-4-deficient mice.},
	journal = {J Immunol},
	volume = {158},
	number = {11},
	year = {1997},
	month = {1997 Jun 1},
	pages = {5091-4},
	abstract = {Mice lacking CTLA-4 develop a fatal spontaneous lymphoproliferative disease with massive lymphocytic infiltrates and tissue destruction in many organs. CTLA-4-deficient (-/-) splenocytes and lymph node cells proliferate without added stimuli in vitro. We report here that CTLA4Ig treatment of CTLA-4 -/- mice prevents lymphoproliferation and fatal multiorgan tissue damage in vivo and proliferation of CTLA-4 -/- splenocytes and lymph node cells in vitro. Therefore, stimulation via CD28-B7 interactions appears necessary for CTLA-4 -/- T cell proliferation and the production of lymphoproliferative disease in vivo. When CTLA4Ig treatment is terminated, CTLA-4 -/- T cells become activated and lymphoproliferative disease develops. The lack of long term protective effects of CTLA4Ig treatment suggests that CTLA-4 is needed for the induction and or maintenance of tolerance.},
	keywords = {Animals, Antigens, CD, Antigens, Differentiation, Cell Division, CTLA-4 Antigen, Immune Tolerance, Immunoconjugates, Immunosuppressive Agents, Lymphoproliferative Disorders, Mice, Mice, Knockout},
	issn = {0022-1767},
	author = {Tivol, E A and Boyd, S D and McKeon, S and Borriello, F and Nickerson, P and Strom,T.B. and Sharpe, A. H.}
}
@article {542986,
	title = {Functional consequences of dysregulated B7-1 (CD80) and B7-2 (CD86) expression in B or T lymphocytes of transgenic mice.},
	journal = {J Immunol},
	volume = {159},
	number = {11},
	year = {1997},
	month = {1997 Dec 1},
	pages = {5336-44},
	abstract = {T cell activation and tolerance are regulated by interactions between CD28 or CTLA-4 on T cells and B7 costimulatory molecules on APCs. We have generated transgenic mouse strains that constitutively express B7-1 (CD80) at high levels on B cells or T cells or express B7-2 (CD86) on T lymphocytes to examine the consequences of dysregulated B7 expression on T cell responses. The transgene-derived B7 molecules are functional, because B7-1 transgenic B cells are more efficient APCs than are wild-type B cells, and the activation of B7 transgenic T cells is less dependent on exogenous costimulation than that of wild-type T cells. In vivo, constitutive expression of B7 molecules leads to the elimination of immature B cells. The expression of B7 molecules on thymocytes results in the down-regulation of CD28 expression. However, B7 transgenic mice have normal numbers of mature lymphocytes and mount normal T cell responses following immunization with protein Ag. Neither anergy induction nor superantigen-mediated deletion of T cells is altered by the dysregulated expression of B7-1 or B7-2 on B or T lymphocytes in these transgenic strains. Therefore, functionally significant levels of B7 expressed constitutively on mature lymphocytes are not, by themselves, sufficient to abrogate T cell tolerance or induce autoimmune disease.},
	keywords = {Animals, Antigens, CD, Antigens, CD80, Antigens, CD86, B-Lymphocytes, Immune Tolerance, Membrane Glycoproteins, Mice, Mice, Transgenic, T-Lymphocytes},
	issn = {0022-1767},
	author = {Van Parijs, L and Sethna, M P and Schweitzer, A N and Borriello, F and Sharpe, A. H. and Abbas,A.K.}
}
@article {543001,
	title = {The role of donor and recipient B7-1 (CD80) in allograft rejection.},
	journal = {J Immunol},
	volume = {159},
	number = {3},
	year = {1997},
	month = {1997 Aug 1},
	pages = {1169-73},
	abstract = {Blockade of CD28-mediated T cell costimulatory signals produces effective immunosuppression of a variety of T cell-dependent in vivo immune responses, including autoimmune disorders and transplant rejection. The soluble fusion protein CTLA4Ig, which competitively blocks CD28 ligands B7-1 and B7-2, can prevent allograft and xenograft rejection and in some circumstances induce transplantation tolerance. To determine the relative roles of B7-1 and B7-2 in graft rejection, we have performed islet and cardiac allografts with normal and B7-1(-/-) mice in conjunction with selective blocking reagents. We found that the absence of B7-1 on donor or recipient tissues leads to a slight prolongation of islet allograft survival, but has minimal or no effect on cardiac allograft survival. Allograft function is further prolonged in the islet model when both donor and recipient lack B7-1, although cardiac allograft survival is not prolonged. In the cardiac model, treatment with CTLA4Ig induces long term survival in B7-1(-/-) recipients regardless of donor status. In contrast, anti-B7-2 mAb leads to indefinite allograft survival only when the recipient and donor both lack B7-1, indicating that even in the absence of available B7-2, B7-1 molecules on the donor or recipient cells alone are sufficient to induce graft rejection. These data also indicate that B7-1 and B7-2 are the only CD28 ligands relevant to cardiac allograft rejection in mice.},
	keywords = {Animals, Antigens, CD80, Graft Rejection, Heart Transplantation, Islets of Langerhans Transplantation, Lymphocyte Culture Test, Mixed, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Species Specificity, T-Lymphocytes, Transplantation, Homologous},
	issn = {0022-1767},
	author = {Zheng, X X and Sayegh, M H and Zheng, X G and Li, Y. and Linsley, P S and Peach, R and Borriello, F and Strom,T.B. and Sharpe, A. H. and Turka, L A}
}
@article {543066,
	title = {Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis.},
	journal = {Proc Natl Acad Sci U S A},
	volume = {93},
	number = {8},
	year = {1996},
	month = {1996 Apr 16},
	pages = {3444-9},
	abstract = {The CBFA2 (AML1) gene encodes a DNA-binding subunit of the heterodimeric core-binding factor. The CBFA2 gene is disrupted by the (8;21), (3;21), and (12;21) chromosomal translocations associated with leukemias and myelodysplasias in humans. Mice lacking a CBF alpha 2 protein capable of binding DNA die between embryonic days 11.5 and 12.5 due to hemorrhaging in the central nervous system (CNS), at the nerve/CNS interfaces of cranial and spinal nerves, and in somitic/intersomitic regions along the presumptive spinal cord. Hemorrhaging is preceded by symmetric, bilateral necrosis in these regions. Definitive erythropoiesis and myelopoiesis do not occur in Cbfa2-deficient embryos, and disruption of one copy of the Cbfa2 gene significantly reduces the number of progenitors for erythroid and myeloid cells.},
	keywords = {Animals, Base Sequence, Central Nervous System Diseases, Core Binding Factor Alpha 2 Subunit, DNA Primers, DNA, Complementary, DNA-Binding Proteins, Erythropoiesis, Female, Fetal Death, Gene Targeting, Hematopoiesis, Hemorrhage, Humans, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Molecular Sequence Data, Mutation, Necrosis, Neoplasm Proteins, Pregnancy, Proto-Oncogene Proteins, Proto-Oncogenes, Transcription Factors},
	issn = {0027-8424},
	author = {Wang, Q and Stacy, T and Binder, M and Marin-Padilla, M and Sharpe, A. H. and Speck, N A}
}
@article {543061,
	title = {Infusion of anti-B7.1 (CD80) and anti-B7.2 (CD86) monoclonal antibodies inhibits murine graft-versus-host disease lethality in part via direct effects on CD4+ and CD8+ T cells.},
	journal = {J Immunol},
	volume = {157},
	number = {8},
	year = {1996},
	month = {1996 Oct 15},
	pages = {3250-9},
	abstract = {Efficient T cell proliferation requires costimulation via CD28/B7 or other pathways. Graft-vs-host disease (GVHD) is caused by activated donor T cells. We have found that the infusion of anti-B7.1 (CD80) + anti-B7.2 (CD86) mAb is effective in eliminating GVHD lethality induced by either CD8+ or CD4+ T cells. Donor CD4+ and CD8+ T cell expansion was inhibited by almost 100-fold as measured by enumerating thoracic duct lymphocytes (TDL) obtained early post-transplant. TDL retained anti-host responsiveness indicating that not all T cells were anergic. Although anti-CD80 or anti-CD86 mAb individually were ineffective in preventing CD8+ T cell GVHD lethality, each mAb was partially effective in CD4+ T cell-mediated GVHD. Because CD80 expression was found to be up-regulated on donor CD4+ TDL post-transplant, the GVHD capacity of donor CD4+ T cells deficient in CD80 was tested and found to be reduced similarly to that seen with anti-CD80 mAb. These studies demonstrate that anti-CD80 + anti-CD86 mAb infusion is effective in preventing GVHD lethality by inhibiting donor CD4+ or CD8+ T cell expansion and provide the first evidence that CD80 expression on donor T cells is critical for optimal GVHD lethality.},
	keywords = {Animals, Antibodies, Monoclonal, Antigens, CD, Antigens, CD80, Antigens, CD86, Bone Marrow Transplantation, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Graft vs Host Disease, Histocompatibility Antigens Class II, Infusions, Intravenous, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Mice, SCID},
	issn = {0022-1767},
	author = {Blazar, B R and Sharpe, A. H. and Taylor, P A and Panoskaltsis-Mortari, A and Gray, G S and Korngold, R and Vallera, D A}
}
@article {543056,
	title = {The CBFbeta subunit is essential for CBFalpha2 (AML1) function in vivo.},
	journal = {Cell},
	volume = {87},
	number = {4},
	year = {1996},
	month = {1996 Nov 15},
	pages = {697-708},
	abstract = {The CBFbeta subunit is the non-DNA-binding subunit of the heterodimeric core-binding factor (CBF). CBFbeta associates with DNA-binding CBFalpha subunits and increases their affinity for DNA. Genes encoding the CBFbeta subunit (CBFB) and one of the CBFalpha subunits (CBFA2, otherwise known as AML1) are the most frequent targets of chromosomal translocations in acute leukemias in humans. We and others previously demonstrated that homozygous disruption of the mouse Cbfa2 (AML1) gene results in embryonic lethality at midgestation due to hemorrhaging in the central nervous system and blocks fetal liver hematopoiesis. Here we demonstrate that homozygous mutation of the Cbfb gene results in the same phenotype. Our results demonstrate that the CBFbeta subunit is required for CBFalpha2 function in vivo.},
	keywords = {Alleles, Animals, Blood Cells, Central Nervous System, Core Binding Factor Alpha 2 Subunit, Core Binding Factor beta Subunit, Crosses, Genetic, DNA-Binding Proteins, Embryo, Mammalian, Gene Dosage, Genes, Lethal, Genotype, Hematopoiesis, Hemorrhage, In Situ Hybridization, Liver, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Mutant Strains, Mutagenesis, Phenotype, Polymerase Chain Reaction, Protein Binding, Proto-Oncogene Proteins, RNA, Messenger, Stem Cells, Transcription Factor AP-2, Transcription Factors},
	issn = {0092-8674},
	author = {Wang, Q and Stacy, T and Miller, J D and Lewis, A F and Gu, T L and Huang, X. and Bushweller, J H and Bories, J C and Alt, F W and Ryan, G and Liu, P P and Wynshaw-Boris, A and Binder, M and Mar{\'\i}n-Padilla, M and Sharpe, A. H. and Speck, N A}
}
@article {543036,
	title = {Costimulation and autoimmunity.},
	journal = {Curr Opin Immunol},
	volume = {8},
	number = {6},
	year = {1996},
	month = {1996 Dec},
	pages = {822-30},
	abstract = {The past year has seen significant advances in our understanding of the role of the B7-CD28/CTLA-4 pathway in T cell activation and self-tolerance. Recent studies have demonstrated that CTLA-4 is a critical negative regulator of T cell activation and autoreactivity, revealing a previously unsuspected means by which costimulation is involved in the maintenance and breakdown of self-tolerance. Manipulation of this costimulatory pathway in animal models of autoimmunity has shown an important role for this pathway in both the initiation and progression of autoimmune diseases.},
	keywords = {Animals, Autoimmune Diseases, Autoimmunity, Humans, Lymphocyte Activation},
	issn = {0952-7915},
	author = {Tivol, E A and Schweitzer, A N and Sharpe, A. H.}
}
@article {543051,
	title = {Late virus replication events in microglia are required for neurovirulent retrovirus-induced spongiform neurodegeneration: evidence from neural progenitor-derived chimeric mouse brains.},
	journal = {J Virol},
	volume = {70},
	number = {12},
	year = {1996},
	month = {1996 Dec},
	pages = {8896-907},
	abstract = {CasBrE is a neurovirulent murine retrovirus which induces a spongiform myeloencephalopathy in susceptible mice. Genetic mapping studies have indicated that sequences responsible for neurovirulence reside within the env gene. To address the question of direct envelope protein neuroxicity in the central nervous system (CNS), we have generated chimeric mice expressing the CasBrE envelope protein in cells of neuroectodermal origin. Specifically, the multipotent neural progenitor cell line C17.2 was engineered to express the CasBrE env gene as either gp70/p15E (CasE) or gp70 alone (CasES). CasE expression in these cells resulted in complete (>10(5)) interference of superinfection with Friend murine leukemia virus clone FB29, whereas CasES expression resulted in a 1.8-log-unit decrease in FB29 titer. Introduction of these envelope-expressing C17.2 cells into the brains of highly susceptible IRW mice resulted in significant engraftment as integral cytoarchitecturally correct components of the CNS. Despite high-level envelope protein expression from the engrafted cells, no evidence of spongiform neurodegeneration was observed. To examine whether early virus replication events were necessary for pathogenesis, C17.2 cells expressing whole virus were transplanted into mice in which virus replication in the host was specifically restricted by Fv-1 to preintegration events. Again, significant C17.2 cell engraftment and infectious virus expression failed to precipitate spongiform lesions. In contrast, transplantation of virus-expressing C17.2 progenitor cells in the absence of the Fv-1 restriction resulted in extensive spongiform neurodegeneration by 2 weeks postengraftment. Cytological examination indicated that infection had spread beyond the engrafted cells, and in particular to host microglia. Spongiform neuropathology in these animals was directly correlated with CasBrE env expression in microglia rather than expression from neural progenitor cells. These results suggest that the envelope protein of CasBrE is not itself neurotoxic but that virus infectious events beyond binding and fusion in microglia are necessary for the induction of CNS disease.},
	keywords = {Animals, Base Sequence, Brain, Cell Line, Central Nervous System, DNA, Viral, Gene Expression, Gene Products, gag, Mice, Microglia, Molecular Sequence Data, Prion Diseases, Retroviridae, Retroviridae Proteins, Oncogenic, Viral Envelope Proteins, Virulence, Virus Replication},
	issn = {0022-538X},
	author = {Lynch, W P and Snyder, E Y and Qualtiere, L and Portis, J L and Sharpe, A. H.}
}
@article {543041,
	title = {A novel role for the beta 2 integrin CD11b/CD18 in neutrophil apoptosis: a homeostatic mechanism in inflammation.},
	journal = {Immunity},
	volume = {5},
	number = {6},
	year = {1996},
	month = {1996 Dec},
	pages = {653-66},
	abstract = {In mice selectively deficient in CD11b/CD18, a beta 2 integrin, chemoattractant-induced leukocyte adhesion to microvascular endothelium in vivo was reduced. Paradoxically, thioglycollate-induced neutrophil accumulation in the peritoneal cavity was increased and was associated with a significant delay in apoptosis of extravasated cells. The extravasated cells had a near absence of neutrophil phagocytosis and a reduction in oxygen free radical generation, which may contribute to the observed defect in apoptosis. This is supported by our in vitro studies, in which phagocytosis of opsonized particles by human neutrophils rapidly induced apoptosis that could be blocked with CD11b/ CD18 antibodies. Reactive oxygen species are the intracellular link in this process: phagocytosis-induced apoptosis was blocked both in neutrophils treated with the flavoprotein inhibitor diphenylene iodonium and in neutrophils from patients with chronic granulomatous disease, which lack NADPH oxidase. Thus, CD11b/CD18 plays a novel and unsuspected homeostatic role in inflammation by accelerating the programmed elimination of extravasated neutrophils.},
	keywords = {Animals, Antigens, CD18, Apoptosis, Blood Cell Count, Granulomatous Disease, Chronic, Homeostasis, Humans, Inflammation, Integrins, Macrophage-1 Antigen, Mice, Mice, Mutant Strains, Models, Immunological, NADPH Oxidase, Neutrophils, Opsonin Proteins, Peritonitis, Phagocytosis, Reactive Oxygen Species, Respiratory Burst, Thioglycolates},
	issn = {1074-7613},
	author = {Coxon, A and Rieu, P and Barkalow, F J and Askari, S and Sharpe, A. H. and von Andrian, U. H. and Arnaout,M.A. and Mayadas, T N}
}
@article {543046,
	title = {Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation.},
	journal = {Immunity},
	volume = {5},
	number = {6},
	year = {1996},
	month = {1996 Dec},
	pages = {537-49},
	abstract = {Mice homozygous for an Ikaros null mutation display distinct defects in the development of fetal and adult lymphocytes. Fetal T lymphocytes, and fetal and adult B lymphocytes and their earliest progenitors are absent. Postnatally, hematopoietic stem cells give rise to thymocyte precursors that undergo aberrant differentiation into the CD4 lineage and clonal expansion. The lack of NK cells and some gamma delta T cell subsets and a large reduction in thymic dendritic APCs suggest that Ikaros is essential for establishing early branch points in the postnatal T cell pathway. The lymphoid defects detected in Ikaros null mice reveal critical molecular differences between fetal and postnatal hematopoietic progenitors that dictate their ability to give rise to T cells. These studies also establish Ikaros as a tumor suppressor gene acting during thymocyte differentiation. Phenotypic comparison of this null mutation with a severe dominant-negative Ikaros mutation identifies molecular redundancy in the postnatal hemolymphoid system.},
	keywords = {Animals, Antigens, CD4, Bone Marrow, Bone Marrow Cells, Cell Differentiation, Clone Cells, Dendritic Cells, DNA-Binding Proteins, Erythropoiesis, Exons, Ikaros Transcription Factor, Liver, Lymphocyte Activation, Lymphocytes, Lymphoid Tissue, Mice, Mice, Mutant Strains, Mutation, Protein Biosynthesis, Receptors, Antigen, T-Cell, gamma-delta, Sequence Deletion, Spleen, T-Lymphocyte Subsets, Thymus Gland, Transcription Factors},
	issn = {1074-7613},
	author = {Wang, J H and Nichogiannopoulou, A and L. Wu and Sun, L and Sharpe, A. H. and Bigby, M and Georgopoulos, K}
}
@article {543111,
	title = {Reciprocal expression of co-stimulatory molecules, B7-1 and B7-2, on murine T cells following activation.},
	journal = {Eur J Immunol},
	volume = {25},
	number = {1},
	year = {1995},
	month = {1995 Jan},
	pages = {207-11},
	abstract = {The co-stimulatory B7 molecules (B7-1 and B7-2) are expressed on professional antigen-presenting cells in mice. In this study, we demonstrate that B7-1 (CD80) and B7-2 (CD86) are also expressed on murine T cells in the absence of major histocompatibility complex class II molecules. The temporal expression of these two molecules on T cells varies with the state of activation where resting T cells express B7-2 but show little or no expression of B7-1. Following activation, B7-2 expression is down-regulated and there is a concomitant increase in the expression of B7-1 on the cell surface which peaks at about 72 h. Thus these two co-stimulatory molecules are reciprocally expressed on the T cell surface. This pattern of expression of B7-1 and B7-2 on T cells suggests that these two molecules may have different roles in the generation and regulation of immune responses.},
	keywords = {Amino Acid Sequence, Animals, Antibodies, Monoclonal, Antigens, CD, Antigens, CD80, Antigens, CD86, Clone Cells, Female, Flow Cytometry, Fluorescent Antibody Technique, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred Strains, Molecular Sequence Data, Myelin Basic Protein, T-Lymphocytes},
	issn = {0014-2980},
	doi = {10.1002/eji.1830250134},
	author = {Prabhu Das, M R and Zamvil, S S and Borriello, F and Weiner, H. L. and Sharpe, A. H. and Kuchroo, V K}
}
@article {543086,
	title = {Analysis of lymphocyte costimulation in vivo using transgenic and {\textquoteright}knockout{\textquoteright} mice.},
	journal = {Curr Opin Immunol},
	volume = {7},
	number = {3},
	year = {1995},
	month = {1995 Jun},
	pages = {389-95},
	abstract = {The use of transgenic technologies in the functional evaluation of the contributions of costimulatory pathways to T-cell activation in vivo has recently undergone a rapid expansion. During the past two years, mice deficient in costimulatory molecules and their receptors have been generated. These mice have revealed novel and critical in vivo functions of costimulatory pathways and have provided valuable models in which to test therapeutic strategies involving costimulatory pathway blockade. Transgenic mice constitutively expressing costimulatory molecules have provided insights into their role in peripheral tolerance.},
	keywords = {Animals, Antigens, CD, Antigens, CD11, Antigens, CD18, Antigens, CD2, Antigens, CD28, Antigens, CD29, Antigens, CD40, Antigens, CD58, Antigens, CD80, Antigens, Differentiation, Cell Adhesion Molecules, Cell Communication, CTLA-4 Antigen, Immunoconjugates, Integrin alpha4beta1, Integrins, Intercellular Adhesion Molecule-1, Lymphocyte Activation, Lymphocyte Function-Associated Antigen-1, Mice, Mice, Knockout, Mice, Transgenic, Receptors, Immunologic, Receptors, Lymphocyte Homing, Receptors, Very Late Antigen, Signal Transduction, Vascular Cell Adhesion Molecule-1},
	issn = {0952-7915},
	author = {Sharpe, A. H.}
}
@article {543076,
	title = {Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3.},
	journal = {Science},
	volume = {270},
	number = {5237},
	year = {1995},
	month = {1995 Nov 3},
	pages = {794-7},
	abstract = {Biochemical studies of signaling mediated by many cytokine and growth factor receptors have implicated members of the Jak family of tyrosine kinases in these pathways. Specifically, Jak3 has been shown to be associated with the interleukin-2 (IL-2) receptor gamma chain, a component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. Mice lacking Jak3 showed a severe block in B cell development at the pre-B stage in the bone marrow. In contrast, although the thymuses of these mice were small, T cell maturation progressed relatively normally. In response to mitogenic signals, peripheral T cells in Jak3-deficient mice did not proliferate and secreted small amounts of IL-2. These data demonstrate that Jak3 is critical for the progression of B cell development in the bone marrow and for the functional competence of mature T cells.},
	keywords = {Animals, Antigens, CD, Antigens, CD43, Antigens, CD45, B-Lymphocytes, Bone Marrow Cells, CD4-Positive T-Lymphocytes, Gene Targeting, Immunoglobulin M, Interleukin-2, Janus Kinase 3, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Protein-Tyrosine Kinases, Sialoglycoproteins, Spleen, Stem Cells, T-Lymphocyte Subsets, T-Lymphocytes},
	issn = {0036-8075},
	author = {Thomis, D C and Gurniak, C B and Tivol, E and Sharpe, A. H. and Berg, L J}
}
@article {543071,
	title = {Differential expression of alternate mB7-2 transcripts.},
	journal = {J Immunol},
	volume = {155},
	number = {12},
	year = {1995},
	month = {1995 Dec 15},
	pages = {5490-7},
	abstract = {The murine B7-2 (mB7-2) costimulatory molecule is expressed on APCs early during the course of an immune response, suggesting that it may play a pivotal role in the decision between T cell activation and anergy. Murine B7-2 mRNA displays a restricted pattern of expression; it is inducible in B cells, T cells, NK cells, and dendritic cells, but constitutively expressed in unstimulated monocytes. The constitutive and inducible expression of mB7-2 on distinct cell types indicates that mB7-2 is regulated differentially. To further characterize mB7-2 transcripts, we employed 5{\textquoteright} rapid amplification of cDNA ends and reverse transcriptase-PCR to examine transcripts expressed in a variety of types of APCs and analyzed the genomic organization of the mB7-2 gene. We report here that the mB7-2 locus consists of 12 exons and demonstrate that exons 1 through 5 can be used in alternative fashions to produce five distinct transcripts, differing in their 5{\textquoteright} untranslated and signal regions. The expression of these transcripts differs in distinct types of APCs and is modulated by stimuli that activate B cells. These results demonstrate that mB7-2 transcripts are differentially regulated in a tissue-specific fashion and in response to activation stimuli.},
	keywords = {Alternative Splicing, Amino Acid Sequence, Animals, Antigen-Presenting Cells, Antigens, CD, Antigens, CD86, Ascitic Fluid, B-Lymphocytes, Base Sequence, Exons, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Molecular Sequence Data, Polymerase Chain Reaction, Promoter Regions, Genetic, RNA Processing, Post-Transcriptional, RNA, Messenger, Spleen, Transcription, Genetic},
	issn = {0022-1767},
	author = {Borriello, F and Oliveros, J and Freeman, G. J. and Nadler,L.M. and Sharpe, A. H.}
}
@article {543106,
	title = {Genomic organization of the gene coding for the costimulatory human B-lymphocyte antigen B7-2 (CD86).},
	journal = {Immunogenetics},
	volume = {42},
	number = {2},
	year = {1995},
	month = {1995},
	pages = {85-9},
	abstract = {The generation of an antigen-specific T-cell response requires that the T lymphocyte receive two signals from the antigen presenting cell. The specificity of this response is provided by antigen presented to the T lymphocyte and involves stimulation of the T lymphocyte via the T-cell receptor (TCR)/CD3 complex. The second, or costimulatory signal, can be provided by ligation of the B-lymphocyte activation antigens B7-1 (CD80) and B7.2 (CD86) to TCR antigen CD28. The cDNAs for both CD80 and CD86 have been isolated and are predicted to encode type 1 membrane proteins of the immunoglobulin (Ig) superfamily. The predicted protein is composed of a signal peptide followed by two Ig-like extracellular domains, a transmembrane domain, and a cytoplasmic tail. Here we report that the genomic organization of CD86 reflects its functional structure, and is similar to that found for CD80. The gene is composed of eight exons which span more than 22 kilobases. The predicted protein functional domains of signal peptide, extracellular IgV- and IgC-like regions, and transmembrane domain coincide with the genomic structure. Two independent sequences had been reported for CD86 cDNA which differed in their 5{\textquoteright}untranslated (UT) regions. We find CD86 exons 1 and 2 correspond to these alternate 5{\textquoteright}UT sequences. Splicing of exon 1 or 2 with the signal peptide encoding exon 3 would produce mRNA transcripts complementary to the reported cDNA clones. Exons 4 and 5 correspond to IgV- and IgC-like extracellular domains, respectively. Exon 6 encodes the transmembrane region and beginning of the cytoplasmic tail. Exons 7 and 8 encode the remainder of the cytoplasmic tail and 3{\textquoteright}UT sequences.},
	keywords = {Amino Acid Sequence, Antigens, CD, Antigens, CD80, Antigens, CD86, Base Sequence, DNA Primers, DNA, Complementary, Exons, Humans, Introns, Membrane Glycoproteins, Molecular Sequence Data, RNA, Messenger},
	issn = {0093-7711},
	author = {Jellis, C L and Wang, S S and Rennert, P and Borriello, F and Sharpe, A. H. and Green, N R and Gray, G S}
}
@article {543101,
	title = {Hemostatic, inflammatory, and fibroblast responses are blunted in mice lacking gelsolin.},
	journal = {Cell},
	volume = {81},
	number = {1},
	year = {1995},
	month = {1995 Apr 7},
	pages = {41-51},
	abstract = {Gelsolin, an 82 kDa actin-binding protein, has potent actin filament-severing activity in vitro. To investigate the in vivo function of gelsolin, transgenic gelsolin-null (Gsn-) mice were generated and found to have normal embryonic development and longevity. However, platelet shape changes are decreased in Gsn- mice, causing prolonged bleeding times. Neutrophil migration in vivo into peritoneal exudates and in vitro is delayed. Gsn- dermal fibroblasts have excessive actin stress fibers and migrate more slowly than wild-type fibroblasts, but have increased contractility in vitro. These observations establish the requirement of gelsolin for rapid motile responses in cell types involved in stress responses such as hemostasis, inflammation, and wound healing. Neither gelsolin nor other proteins with similar actin filament-severing activity are expressed in early embryonic cells, indicating that this mechanism of actin filament dynamics is not essential for motility during early embryogenesis.},
	keywords = {Actins, Animals, Blood Platelets, Cell Movement, Cells, Cultured, Fetus, Fibroblasts, Gelsolin, Gene Expression Regulation, Developmental, Hemostasis, Inflammation, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Neutrophils, RNA, Messenger, Stem Cells, Wound Healing},
	issn = {0092-8674},
	author = {Witke, W and Sharpe, A. H. and Hartwig, J. H. and Azuma, T and Stossel, T. P. and Kwiatkowski, D J}
}
@article {543091,
	title = {Lethal beta-thalassaemia in mice lacking the erythroid CACCC-transcription factor EKLF.},
	journal = {Nature},
	volume = {375},
	number = {6529},
	year = {1995},
	month = {1995 May 25},
	pages = {318-22},
	abstract = {Globin genes are regulated in a tissue-specific and developmental stage-specific manner, with the beta-globin gene being the last to be activated in the beta-gene cluster. CACCC-nucleotide sequences, which bind multiple nuclear proteins, including ubiquitously expressed Sp1 and erythroid Kr{\"u}ppel-like factor (EKLF), are among the cis-regulatory sequences critical for transcription of globin and non-globin erythroid-expressed genes. To determine the function of EKLF in vivo, we created mice deficient in EKLF by gene targeting. These embryos die of anaemia during fetal liver erythropoiesis and show the molecular and haematological features of beta-globin deficiency, found in beta-thalassaemia. Although it is expressed at all stages, EKLF is not required for yolk sac erythropoiesis, erythroid commitment or expression of other potential target genes. Its stage-specific and beta-globin-gene-specific requirement suggests that EKLF may facilitate completion of the fetal-to-adult (haemoglobin gamma to beta) switch in humans.},
	keywords = {Anemia, Animals, Base Sequence, beta-Thalassemia, Cell Line, DNA, DNA-Binding Proteins, Egg Yolk, Erythropoiesis, Female, Fetal Death, Gene Targeting, Genes, Switch, Globins, Kruppel-Like Transcription Factors, Liver, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Molecular Sequence Data, Mutagenesis, Phenotype, Transcription Factors, Zinc Fingers},
	issn = {0028-0836},
	doi = {10.1038/375318a0},
	author = {Perkins, A C and Sharpe, A. H. and Orkin, S H}
}
@article {543081,
	title = {Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4.},
	journal = {Immunity},
	volume = {3},
	number = {5},
	year = {1995},
	month = {1995 Nov},
	pages = {541-7},
	abstract = {The B7-CD28/CTLA-4 costimulatory pathway can provide a signal pivotal for T cell activation. Signaling through this pathway is complex due to the presence of two B7 family members, B7-1 and B7-2, and two counterreceptors, CD28 and CTLA-4. Studies with anti-CTLA-4 monoclonal antibodies have suggested both positive and negative roles for CTLA-4 in T cell activation. To elucidate the in vivo function of CTLA-4, we generated CTLA-4-deficient mice. These mice rapidly develop lymphoproliferative disease with multiorgan lymphocytic infiltration and tissue destruction, with particularly severe myocarditis and pancreatitis, and die by 3-4 weeks of age. The phenotype of the CTLA-4-deficient mouse strain is supported by studies that have suggested a negative role for CTLA-4 in T cell activation. The severe phenotype of mice lacking CTLA-4 implies a critical role for CTLA-4 in down-regulating T cell activation and maintaining immunologic homeostasis. In the absence of CTLA-4, peripheral T cells are activated, can spontaneously proliferate, and may mediate lethal tissue injury.},
	keywords = {Animals, Antigens, CD, Antigens, Differentiation, Base Sequence, Cells, Cultured, CTLA-4 Antigen, Cytokines, DNA Primers, Down-Regulation, Immunoconjugates, Immunohistochemistry, Lymphocyte Activation, Lymphoid Tissue, Lymphoproliferative Disorders, Mice, Mice, Mutant Strains, Mice, Transgenic, Molecular Sequence Data, T-Lymphocytes, Viscera},
	issn = {1074-7613},
	author = {Tivol, E A and Borriello, F and Schweitzer, A N and Lynch, W P and Bluestone, J A and Sharpe, A. H.}
}
@article {543096,
	title = {Transgenic mice for the preparation of hygromycin-resistant primary embryonic fibroblast feeder layers for embryonic stem cell selections.},
	journal = {Nucleic Acids Res},
	volume = {23},
	number = {7},
	year = {1995},
	month = {1995 Apr 11},
	pages = {1273-5},
	keywords = {Animals, Base Sequence, Cells, Cultured, Cinnamates, DNA, Drug Resistance, Fibroblasts, Hygromycin B, Mice, Mice, Inbred C57BL, Mice, Transgenic, Molecular Sequence Data, Stem Cells},
	issn = {0305-1048},
	author = {Johnson, K A and Lerner, C P and Di Lacio, L C and Laird, P W and Sharpe, A. H. and Simpson, E M}
}
@article {543116,
	title = {Characterization of the murine B7-1 genomic locus reveals an additional exon encoding an alternative cytoplasmic domain and a chromosomal location of chromosome 16, band B5.},
	journal = {J Immunol},
	volume = {153},
	number = {11},
	year = {1994},
	month = {1994 Dec 1},
	pages = {5038-48},
	abstract = {The murine B7-1 (mB7-1) molecule expressed on APCs delivers a costimulatory signal for T cell activation through its T cell counter-receptor CD28, resulting in T cell proliferation and IL-2 production. Signaling through the TCR in the absence of CD28 signaling results in T cell anergy. We have analyzed the genomic structure of mB7-1 and here describe the identification of a previously unrecognized sixth exon at the far 3{\textquoteright} end of the locus, which encodes an alternative cytoplasmic domain. Reverse transcriptase-PCR amplification of mB7-1 transcripts demonstrates that exon 6 is functionally spliced to the transmembrane-encoding exon 4. Furthermore, using 5{\textquoteright} rapid amplification of cDNA ends, we determined that the 5{\textquoteright}-untranslated region extends over 1505 bp beyond the previously reported transcriptional start site. In addition, we report the chromosomal location of mB7-1 to chromosome 16, band B5.},
	keywords = {Alternative Splicing, Amino Acid Sequence, Animals, Antigens, CD80, Base Sequence, Blotting, Northern, Chromosome Mapping, Exons, Genomic Library, Humans, In Situ Hybridization, Mice, Mice, Inbred AKR, Mice, Inbred DBA, Molecular Sequence Data, Nucleic Acid Hybridization, Polymerase Chain Reaction, RNA, Messenger, Transcription, Genetic},
	issn = {0022-1767},
	author = {Borriello, F and Freeman, G. J. and Edelhoff, S and Disteche, C M and Nadler,L.M. and Sharpe, A. H.}
}
@article {543121,
	title = {A negative regulatory function of B7 revealed in B7-1 transgenic mice.},
	journal = {Immunity},
	volume = {1},
	number = {5},
	year = {1994},
	month = {1994 Aug},
	pages = {415-21},
	abstract = {To analyze the functions of T cell costimulators in vivo, we have constructed a transgenic mouse strain that constitutively expresses murine B7-1 on mature B cells. Antibody responses to T-dependent hapten-protein conjugates and serum immunoglobulin levels are markedly depressed in B7-1 transgenic mice. This immune deficiency is not due to an intrinsic B cell defect, as antibody responses to T-independent hapten conjugates are normal. Furthermore, treatment with anti-B7-1 restores the capacity of transgenic mice to respond to hapten-protein conjugates, demonstrating that the deficient antibody responses are directly attributable to the expression of B7-1. These results suggest that the temporally regulated expression of costimulators such as B7-1 may contribute to either initiation or down-regulation (feedback inhibition) of T-dependent immune responses in vivo, and that the inhibitory function is dominant in transgenic mice that constitutively express high levels of this costimulator.},
	keywords = {Animals, Antibody Formation, Antigens, CD80, B-Lymphocytes, Base Sequence, Gene Expression, Mice, Mice, Transgenic, Molecular Sequence Data},
	issn = {1074-7613},
	author = {Sethna, M P and Van Parijs, L and Sharpe, A. H. and Abbas,A.K. and Freeman, G. J.}
}
@article {543126,
	title = {Retroviral spongiform degenerative disease produced by the murine neurotropic retrovirus Cas-Br-E.},
	journal = {Dev Biol Stand},
	volume = {80},
	year = {1993},
	month = {1993},
	pages = {45-52},
	abstract = {The murine neurotropic retrovirus Cas-Br-E causes a non-inflammatory spongiform neurodegenerative disease involving the spinal cord, brainstem and cerebellum, manifest as a progressive, fatal lower motor neuron disease. Using in utero infection of mid-gestation mouse embryos, we have developed a rapid model for the study of this disease. Infection of mid-gestation embryos caused paralysis and death within 25 days after birth, in contrast to virus-infected neonates, which develop disease only after three months. We have found that this model is well suited not only to the study of neurovirulence but also to the rapid, quantitative assessment of treatment strategies in the CNS. The drug 3{\textquoteright}-azido-3{\textquoteright}-deoxythymidine (AZT) was found to cross the placental barrier effectively and markedly retarded the onset and course of disease, when given to infected embryos through the drinking water of pregnant females. CNS injury seems to be due to a direct viral action, but the precise target cells of the virus are uncertain. The identification of the viral target cells is complicated by the presence of numerous endogenous retroviruses in the mouse genome, as well as difficulties with identifying infected cell types by morphology alone. To identify Cas-Br-E-infected cells precisely, we have performed in situ hybridization studies using a Cas-Br-E-specific riboprobe and found that infected cells are in regions of the CNS in which spongiform lesions develop and in regions without any obvious pathology.(ABSTRACT TRUNCATED AT 250 WORDS)},
	keywords = {Animals, Animals, Wild, Central Nervous System, Disease Models, Animal, Female, Fetal Diseases, Gammaretrovirus, Gestational Age, In Situ Hybridization, Mice, Microinjections, Motor Neuron Disease, Pregnancy, Retroviridae Infections, Rodent Diseases, Zidovudine},
	issn = {0301-5149},
	author = {Sharpe, A. H. and Jaenisch, R}
}
@article {543131,
	title = {Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system.},
	journal = {Cell},
	volume = {69},
	number = {5},
	year = {1992},
	month = {1992 May 29},
	pages = {737-49},
	abstract = {We have generated mice carrying a mutation of the gene encoding the low affinity NGF receptor p75NGFR by targeted mutation in embryonic stem cells. Mice homozygous for the mutation were viable and fertile. Immunohistochemical analyses of the footpad skin of mutant mice revealed markedly decreased sensory innervation by calcitonin gene-related peptide- and substance P-immunoreactive fibers. The defective innervation was correlated with loss of heat sensitivity and associated with the development of ulcers in the distal extremities. Complicated by secondary bacterial infection, the ulcers progressed to toenail and hair loss. Crossing a human transgene encoding p75NGFR into the mutant animals rescued the absent heat sensitivity and the occurrence of skin ulcers and increased the density of neuropeptide-immunoreactive sensory innervation of footpad skin. The mutation in the gene encoding p75NGFR did not decrease the size of sympathetic ganglia or the density of sympathetic innervation of the iris or salivary gland. Our results suggest that p75NGFR has an important role in the development and function of sensory neurons.},
	keywords = {Animals, Blotting, Western, Cell Line, Female, Iris, Male, Mice, Mice, Inbred BALB C, Mutation, Nerve Growth Factors, Neurons, Afferent, Nucleotide Mapping, Receptors, Cell Surface, Receptors, Nerve Growth Factor, Salivary Glands, Skin},
	issn = {0092-8674},
	author = {Lee, K F and Li, E and Huber, L J and Landis, S C and Sharpe, A. H. and Chao, M V and Jaenisch, R}
}
@article {543136,
	title = {Transplacental antiretroviral therapy with 9-(2-phosphonylmethoxyethyl)adenine is embryotoxic in transgenic mice.},
	journal = {J Acquir Immune Defic Syndr},
	volume = {4},
	number = {9},
	year = {1991},
	month = {1991},
	pages = {833-8},
	abstract = {Transgenic Mov-14 mice, which carry the provirus of Moloney murine leukemia virus (Mo-MuLV) in the germ line and begin to produce infectious virus on embryonic day 14, were used to evaluate the ability of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) to cross the placenta and protect embryos from viremia. We have used the Mov-14 model previously to demonstrate the antiviral efficacy and lack of teratogenicity of transplacental therapy with 3{\textquoteright}-azido-3{\textquoteright}-deoxythymidine (zidovudine, ZDV). PMEA was administered to pregnant females by daily intraperitoneal injection or by osmotic pump. In contrast to ZDV, PMEA was either noneffective in preventing viremia in the offspring or embryotoxic, depending on the dose. The specific toxic effects seen were resorption of pregnancy, low birth weight, and neonatal death. Histopathological analysis of neonatal mice exposed to PMEA showed severe lymphoid depletion of the thymus. We conclude that PMEA therapy is contraindicated for use during pregnancy.},
	keywords = {Adenine, Animals, Antiviral Agents, Embryo, Mammalian, Female, Fetal Resorption, Litter Size, Maternal-Fetal Exchange, Mice, Mice, Inbred C57BL, Mice, Transgenic, Moloney murine leukemia virus, Organophosphonates, Pregnancy, Viremia, Zidovudine},
	issn = {0894-9255},
	author = {Lee, J S and Mullaney, S and Bronson, R and Sharpe, A. H. and Jaenisch, R and Balzarini, J and De Clercq, E and Ruprecht, R M}
}
@article {543151,
	title = {Analysis of 3{\textquoteright}-azido-3{\textquoteright}-deoxythymidine levels in tissues and milk by isocratic high-performance liquid chromatography.},
	journal = {J Chromatogr},
	volume = {528},
	number = {2},
	year = {1990},
	month = {1990 Jun 29},
	pages = {371-83},
	abstract = {A sensitive high-performance liquid chromatographic (HPLC) assay was established to analyze levels of the antiretroviral agent 3{\textquoteright}-azido-3{\textquoteright}-deoxythymidine (AZT, zidovudine) in serum, milk and tissue extracts. After methanol precipitation, serum samples could be injected directly into the HPLC apparatus, whereas tissue extracts required further clarification. Recovery of AZT was virtually complete. Isocratic elution with a mobile phase consisting of 6\% acetonitrile and 0.1 M ammonium acetate, pH adjusted to 4.5 with glacial acetic acid, resulted in good resolution of AZT and its metabolites; retention times for AZT and the internal standard, p-nitrophenol, were 20 and 37 min, respectively. Using this method, we have demonstrated that AZT crosses both the blood-brain and placental barriers and is excreted into milk at high levels.},
	keywords = {Animals, Brain Chemistry, Chromatography, High Pressure Liquid, Female, Fetus, Humans, Lactation, Male, Maternal-Fetal Exchange, Mice, Mice, Inbred BALB C, Mice, Transgenic, Milk, Milk, Human, Pregnancy, Zidovudine},
	author = {Ruprecht, R M and Sharpe, A. H. and Jaenisch, R and Trites, D}
}
@article {543156,
	title = {Reovirus transport--studies using lymphocytosis promoting factor.},
	journal = {Pathobiology},
	volume = {58},
	number = {4},
	year = {1990},
	month = {1990},
	pages = {185-92},
	abstract = {To explore how bacteria and their products may modulate viral infection, we investigated the effect of a well-characterized and highly purified product of Bordetella pertussis, a pertussis toxin, also known as lymphocytosis promoting factor (LPF), on enteric reovirus infection. LPF is known to have a variety of effects, including modulation of circulation and homing of lymphoid cells. When adult mice are inoculated with reovirus type 1 perorally, reovirus first enters the Peyer{\textquoteright}s patches (PP) through M cells, and then spreads to mesenteric lymph nodes (MLN) and spleen with minimal dissemination to other peripheral tissues. In view of the profound effect of LPF on lymphoid tissues, we evaluated whether LPF might influence the early stages of type-1 reovirus infection following peroral inoculation. Pretreatment of adult BALB/c mice with LPF significantly inhibited the spread of reovirus in a manner dependent upon the route of inoculation; LPF inhibited the extra-intestinal spread of virus from PP to MLN after intragastric inoculation; in contrast there was enhancement of the spread of blood-borne viruses to MLN after intravenous inoculation. This result, together with the fact that the efferent lymph from PP reaches MLN, suggests that a proportion of reoviruses were conveyed from PP to MLN in association with lymphoid cells along the lymphatic channels and that LPF affects reovirus, in part, by blocking cell movement.},
	keywords = {Animals, Cell Movement, Gastrointestinal Diseases, Lymph Nodes, Lymphocytes, Mice, Mice, Inbred BALB C, Mice, Nude, Pertussis Toxin, Peyer{\textquoteright}s Patches, Reoviridae Infections, Virulence Factors, Bordetella},
	issn = {1015-2008},
	author = {Sugimoto, M and Sharpe, A. H. and Sato, Y and Greene, M I and Fields, B N}
}
@article {543146,
	title = {Role of abortive retroviral infection of neurons in spongiform CNS degeneration.},
	journal = {Nature},
	volume = {346},
	number = {6280},
	year = {1990},
	month = {1990 Jul 12},
	pages = {181-3},
	abstract = {Retroviruses are involved in several human neurological diseases with varying pathological features. Whether these diseases are due to a direct effect of the virus on nervous system cells is unknown. To gain insight into the pathogenesis of one retroviral neurological disease, we are studying the murine neurotropic retrovirus, Cas-Br-E, which causes lower motor neuron disease associated with spongiform degenerative changes in brain and spinal cord. Central nervous system (CNS) injury seems to be due to direct viral action, but the precise target cells of the virus are uncertain. After blood-borne virus enters the CNS it is found in capillary endothelial cells. No microscopic evidence for virus within glia or neurons has been found in some studies, whereas virus or incomplete particles have been observed in CNS cells in other studies. Here we identify the neuron as a major target for Cas-Br-E in the CNS, suggesting that this disease may be a direct result of viral infection of neurons. We also show that envelope protein (Env, encoded by the env gene), a major determinant of neurovirulence, cannot be detected in neurons but is present in non-neuronal cells, although spliced env messenger RNA is synthesized in CNS tissue. This suggests that a post-transcriptional step in Cas-Br-E Env protein synthesis is impaired and that the neurological disease may be a consequence of abortive replication of virus in neurons. This may explain the failure to find neuronal infection in other neurological diseases by conventional methods of virus detection.},
	keywords = {Animals, Antigens, Viral, Central Nervous System Diseases, Gene Products, env, Mice, Mice, Inbred Strains, Nerve Degeneration, Neurons, Retroviridae, RNA, Messenger, RNA, Viral, Spinal Cord, Virus Replication},
	issn = {0028-0836},
	doi = {10.1038/346181a0},
	author = {Sharpe, A. H. and Hunter, J J and Chassler, P and Jaenisch, R}
}
@article {543141,
	title = {Transgenic mouse model of kidney disease: insertional inactivation of ubiquitously expressed gene leads to nephrotic syndrome.},
	journal = {Cell},
	volume = {62},
	number = {3},
	year = {1990},
	month = {1990 Aug 10},
	pages = {425-34},
	abstract = {Transgenic mouse strains carrying proviruses were generated by exposing mouse embryos to a recombinant retrovirus. Animals carrying a single provirus were intercrossed to derive mice homozygous for a given proviral insertion. Adult mice homozygous for the Mpv17 integration developed nephrotic syndrome and chronic renal failure. Histologically, affected kidneys showed progressive glomerular sclerosis. Similar lesions are seen in patients with progressive renal function deterioration. A probe to DNA sequences flanking the provirus detected a 1.7 kb RNA ubiquitously expressed during embryogenesis and in adults with high levels in kidney, brain, and heart. This RNA was not detected in tissues of homozygous animals, suggesting that the provirus interferes with RNA expression. Sequence analysis of the cDNA revealed that the gene encodes a 176 amino acid peptide containing hydrophobic regions, suggesting membrane association of the putative protein. The Mpv17 mutant is a potentially useful experimental system for studying mechanisms leading to renal disorders in man.},
	keywords = {Amino Acid Sequence, Animals, Base Sequence, Blotting, Southern, Chromosome Mapping, Cloning, Molecular, Disease Models, Animal, DNA, DNA Transposable Elements, Female, Genotype, Glomerulonephritis, Glomerulosclerosis, Focal Segmental, Homozygote, Kidney Failure, Chronic, Kidney Glomerulus, Membrane Proteins, Mice, Mice, Inbred Strains, Mice, Transgenic, Microscopy, Electron, Molecular Sequence Data, Mutation, Nephrotic Syndrome, Oligonucleotide Probes, Poly A, Proteins, Restriction Mapping, Retroviridae, RNA, RNA, Messenger},
	issn = {0092-8674},
	author = {Weiher, H and Noda, T and Gray, D A and Sharpe, A. H. and Jaenisch, R}
}
@article {543166,
	title = {Maternal transmission of retroviral disease and strategies for preventing infection of the neonate.},
	journal = {J Virol},
	volume = {63},
	number = {3},
	year = {1989},
	month = {1989 Mar},
	pages = {1049-53},
	abstract = {Moloney murine leukemia virus is efficiently transmitted from viremic mothers to offspring, primarily via virus-containing milk. To determine the level in the infectious process at which an antiviral agent can interfere most effectively with perinatal viral transmission, we examined the effect of the drug 3{\textquoteright}-azido-3{\textquoteright}-deoxythymidine (AZT) on transmission of Moloney murine leukemia virus from viremic mothers to offspring. Although AZT treatment did not affect the titer of virus in milk, it did suppress the development of viremia in all offspring. AZT, however, did not prevent transmission of virus from viremic mothers to 25\% of the offspring, but did lead to a marked reduction in virus load in these infected mice. These results provide evidence for effective antiretroviral therapy during gestation and in the perinatal period and are of potential significance for the management of maternal transmission of human retroviruses.},
	keywords = {Animals, Animals, Newborn, Female, Leukemia, Experimental, Mice, Mice, Inbred BALB C, Milk, Moloney murine leukemia virus, Pregnancy, Pregnancy Complications, Infectious, Spleen, Thymus Gland, Viral Plaque Assay, Zidovudine},
	issn = {0022-538X},
	author = {Sharpe, A. H. and Hunter, J J and Ruprecht, R M and Jaenisch, R}
}
@article {543161,
	title = {The ras and myc oncogenes cooperate in tumor induction in many tissues when introduced into midgestation mouse embryos by retroviral vectors.},
	journal = {Proc Natl Acad Sci U S A},
	volume = {86},
	number = {7},
	year = {1989},
	month = {1989 Apr},
	pages = {2224-8},
	abstract = {Midgestation embryos were infected with replication-defective retroviral vectors that either transduced the myc oncogene, the ras oncogene, or both oncogenes simultaneously. The myc virus induced tumors in diverse organs at a very low frequency and with a long latency period, while approximately 20\% of the mice derived from embryos infected with the ras virus developed tumors in the skin with a latency of 4-8 weeks. In contrast, infection of embryos with the ras/myc double oncogene virus resulted in 27\% of the animals developing rapidly growing and malignant tumors in a great variety of tissues after a median latency period of 2-3 weeks. All tumors were of monoclonal origin, as shown by Southern analysis using the provirus as a molecular marker. Our results are consistent with the hypothesis that the ras and myc oncogenes cooperate in transforming cells, but that additional alterations are necessary for realization of the fully malignant phenotype. Our observations also suggest that a much wider range of cell types become targets for malignant transformation when the embryos are exposed to the myc and the ras oncogenes simultaneously than when exposed to the same oncogenes separately. Infection of mouse embryos with vectors carrying different oncogenes or oncogene combinations may be an efficient and rapid method for evaluating the spectrum of cell types at risk for malignant conversion following mutation of a protooncogene to a transforming gene.},
	keywords = {Animals, Brain Neoplasms, Carcinoma, Squamous Cell, Cell Transformation, Neoplastic, Embryo, Mammalian, Genes, ras, Genetic Vectors, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred Strains, Proto-Oncogenes, Retroviridae, Skin Neoplasms, Transduction, Genetic},
	issn = {0027-8424},
	author = {Compere, S J and Baldacci, P and Sharpe, A. H. and Thompson, T. and Land, H and Jaenisch, R}
}
@article {543171,
	title = {Retroviral transduction of the human c-Ha-ras-1 oncogene into midgestation mouse embryos promotes rapid epithelial hyperplasia.},
	journal = {Mol Cell Biol},
	volume = {9},
	number = {1},
	year = {1989},
	month = {1989 Jan},
	pages = {6-14},
	abstract = {Infection of mouse embryos at 8 days of gestation with a replication-defective retrovirus carrying the human c-Ha-ras-1 oncogene led to efficient and rapid induction of hyperplastic lesions. Twenty-four percent of viable off-spring developed abnormal growths after infection with purified virus. The lesions contained a single integrated provirus and produced viral RNA and the Ha-ras oncogene product (p21). The latency period between the time of infection and appearance of the lesions suggested that secondary alterations in addition to activated ras were necessary for neoplasms to develop. The earliest and most abundant growths were cutaneous and appeared from 4 to 36 weeks of age, with a median of 4 weeks of age. A number of subcutaneous lesions also developed over the same time span but at a median of 18 weeks of age. The rapid development of cutaneous lesions in response to transduction of the ras oncogene contrasts with other studies in which adult skin required secondary treatment with promoters prior to ras induction of epithelial hyperplasia. These results demonstrate that infection of midgestation mouse embryos allows rapid analysis of oncogene potency in skin.},
	keywords = {Animals, Cell Transformation, Viral, DNA, Recombinant, DNA, Viral, Embryo, Mammalian, Epithelium, Female, Genes, ras, Humans, Hyperplasia, Immunoblotting, Mice, Oncogene Protein p21(ras), Oncogene Proteins, Viral, Pregnancy, RNA, Viral, Skin, Transduction, Genetic, Tumor Cells, Cultured},
	issn = {0270-7306},
	author = {Compere, S J and Baldacci, P A and Sharpe, A. H. and Jaenisch, R}
}
@article {543176,
	title = {Maternal transmission of retroviral disease: transgenic mice as a rapid test system for evaluating perinatal and transplacental antiretroviral therapy.},
	journal = {Proc Natl Acad Sci U S A},
	volume = {85},
	number = {24},
	year = {1988},
	month = {1988 Dec},
	pages = {9792-6},
	abstract = {Transgenic mouse strains carrying Moloney murine leukemia virus (Mo-MuLV) in the germ line were found to serve as rapid and quantitative models of in utero and perinatal retroviral infection for evaluating strategies of antiretroviral therapy. In these strains virus activation leads to virus expression, viral spread associated with the development of viremia, and subsequent T-cell leukemia/lymphoma. To test these transgenic strains for their usefulness in evaluating antiretroviral agents, the effect of the drug 3{\textquoteright}-azido-3{\textquoteright}-deoxythymidine (AZT) on the development of viremia and subsequent disease was examined. The assessment of mice for viremia at 1 month of age appeared to be the most useful assay because it was rapid and quantitative. AZT was most effective in preventing viremia in transgenic strains that activate Mo-MuLV after birth and had more variable effects in strains that activate prior to birth. However, in six of seven of the strains examined, AZT led to a marked improvement in survival and reduced the onset of T-cell leukemia/lymphoma. These results provide evidence for effective antiretroviral therapy during gestation and in the perinatal period and are of potential significance for the management of the maternal transmission of human retroviruses.},
	keywords = {Animals, Antiviral Agents, Female, Maternal-Fetal Exchange, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Moloney murine leukemia virus, Pregnancy, Retroviridae Infections, Zidovudine},
	issn = {0027-8424},
	author = {Sharpe, A. H. and Hunter, J J and Ruprecht, R M and Jaenisch, R}
}
@article {543186,
	title = {Adherence to and penetration of the intestinal epithelium by reovirus type 1 in neonatal mice.},
	journal = {Gastroenterology},
	volume = {92},
	number = {1},
	year = {1987},
	month = {1987 Jan},
	pages = {82-91},
	abstract = {In 10-day-old suckling and adult mice, reovirus type 1 adheres selectively to and penetrates membranous epithelial (M) cells. To determine when M cells first appear, when they first transport reovirus, and if reovirus adheres to and is endocytosed by other epithelial cells in the first postnatal week, we examined neonatal mouse intestine by transmission electron microscopy after reovirus type 1 exposure. At 2 days M cells accounted for 0.9\% of dome epithelial cells. By 9 days M cells had increased to 7.4\%. Reovirus type 1 adherence to the surface of villus and dome epithelial cells showed marked variation in 2-6-day-old animals, but by 7 days only a few absorptive cell profiles had adherent reovirus. Adherence to greater than 50\% of M-cell profiles occurred in all but 2 animals, but adherence to the majority of Peyer{\textquoteright}s patch absorptive cell profiles was present only in some 4- and 5-day-old animals. Adherence to a majority of undifferentiated cell profiles occurred in some animals at all ages. Membranous epithelial cells endocytosed reovirus at all ages but only at 2 days did rare villus and dome absorptive cells endocytose reovirus into the apical cytoplasm. Thus, adherence of reovirus to the apical surface of mucosal epithelial cells is nonselective in newborn mice but becomes more selective within the first postnatal week with adherence by day 7 to most M-cell profiles, to a substantial but variable number of undifferentiated cell profiles, but to few absorptive cell profiles.},
	keywords = {Animals, Animals, Newborn, Endocytosis, Intestinal Diseases, Intestinal Mucosa, Mice, Peyer{\textquoteright}s Patches, Reoviridae, Reoviridae Infections},
	issn = {0016-5085},
	author = {Wolf, J L and Dambrauskas, R and Sharpe, A. H. and Trier, J S}
}
@article {543181,
	title = {Retroviruses and mouse embryos: a rapid model for neurovirulence and transplacental antiviral therapy.},
	journal = {Science},
	volume = {236},
	number = {4809},
	year = {1987},
	month = {1987 Jun 26},
	pages = {1671-4},
	abstract = {A murine model in which neurotropic retroviral infection can be studied over short periods of time was developed. Microinjection of Cas-Br-E virus into midgestation mouse embryos caused paralysis and death within 25 days after birth, in contrast to virus-infected neonates which develop disease only after 4 months. To evaluate whether antiviral drugs could cross the placental barrier and influence the course of the disease, the drug 3{\textquoteright}-azido-3{\textquoteright}-deoxythymidine (AZT) was administered to infected embryos through the drinking water of pregnant females. AZT treatment markedly retarded the onset and course of virus-induced central nervous system disease, permitting animals to survive beyond 4 months of age. These results are evidence for effective antiviral treatment during gestation and in the perinatal period and are of potential significance for the management of maternal transmission of the acquired immune deficiency syndrome (AIDS) virus.},
	keywords = {Animals, Animals, Newborn, Antiviral Agents, Central Nervous System Diseases, Female, Fetal Diseases, Gestational Age, Maternal-Fetal Exchange, Mice, Pregnancy, Prenatal Exposure Delayed Effects, Retroviridae, Thymidine, Tumor Virus Infections, Virulence, Zidovudine},
	issn = {0036-8075},
	author = {Sharpe, A. H. and Jaenisch, R and Ruprecht, R M}
}
@article {543191,
	title = {Syngeneic monoclonal internal image anti-idiotopes as prophylactic vaccines.},
	journal = {J Immunol},
	volume = {137},
	number = {9},
	year = {1986},
	month = {1986 Nov 1},
	pages = {2930-6},
	abstract = {A syngeneic monoclonal anti-idiotope that behaves as an internal image of the mammalian reovirus type 3 cellular attachment protein (viral hemagglutinin) was used in the syngeneic host for the induction of a prophylactic anti-viral antibody response. These studies were performed without the aid of co-stimulation by viral antigens. The high stringency of this system enables us to define the maximum constraints on the use of anti-idiotopes as anti-viral vaccines. We have used the murine BALB/c monoclonal IgM anti-idiotope 87.92.6 to study the idiotope and antigen specificity, kinetics, dose dependence, adjuvant, carrier, and valency requirements of anti-idiotope-induced anti-viral antibody responses. These studies show that the production of high titer neutralizing antibody requires a lengthy (60 day) immunization protocol, which includes the use of adjuvant and multivalent anti-idiotope, and is dependent on anti-idiotope concentrations of greater than 50 micrograms. When administered in this manner anti-idiotope can stimulate serotype-specific antibody responses across species barriers at levels comparable with those obtained after inoculation with virus. The practical efficacy of these reagents and procedures is documented by the ability of maternal immunization with anti-idiotope to confer complete protection in neonates from a potentially lethal reovirus type 3 viral infection.},
	keywords = {Animals, Antibodies, Anti-Idiotypic, Antibodies, Monoclonal, Antibody Specificity, Antigens, Antigens, Viral, Dose-Response Relationship, Immunologic, Immunoglobulin Idiotypes, Kinetics, Mammalian orthoreovirus 3, Mice, Reoviridae Infections, Vaccines, Synthetic, Viral Vaccines},
	issn = {0022-1767},
	author = {Gaulton,G.N. and Sharpe, A. H. and Chang, D W and Fields, B N and Greene, M I}
}
@article {543196,
	title = {Cell receptors for the mammalian reovirus. IV. Reovirus-specific cytolytic T cell lines that have idiotypic receptors recognize anti-idiotypic B cell hybridomas.},
	journal = {J Immunol},
	volume = {134},
	number = {4},
	year = {1985},
	month = {1985 Apr},
	pages = {2702-6},
	abstract = {Cytotoxic T lymphocyte (Tc) cell lines specific for reovirus type 3 lysed an uninfected B cell hybridoma line, 87.92.6, that expresses and secretes an anti-idiotypic antibody that reacts with an anti-viral hemagglutinin monoclonal antibody, 9BG5. Monoclonal anti-idiotype 87.92.6 was shown by fluorescence analysis to specifically bind to reovirus Tc and to block reovirus-specific Tc from killing reovirus-infected target cells or the 87.92.6 hybridoma. An anti-LFA-1 monoclonal antibody, M17, interfered with Tc-mediated lysis of reovirus-infected targets and the 87.92.6 cells, indicating the similarity of cellular interactions mediated by LFA-1 structures when Tc bind to virally infected targets or 87.92.6 targets. Together with studies in which anti-H2 or monoclonal idiotypic antibodies were found to interfere with reovirus-specific Tc recognition of virally infected or 87.92.6 targets, these experiments indicate that some reovirus-specific Tc have conformations in their receptor that can be recognized by anti-idiotype.},
	keywords = {Animals, Antibodies, Monoclonal, Antigens, Surface, Antigens, Viral, B-Lymphocytes, Binding, Competitive, Cell Line, Cytotoxicity, Immunologic, Epitopes, Hybridomas, Immunoglobulin Idiotypes, Mammalian orthoreovirus 3, Mice, Mice, Inbred BALB C, Receptors, Antigen, T-Cell, Receptors, Virus, Reoviridae, Reoviridae Infections, T-Lymphocytes, Cytotoxic},
	issn = {0022-1767},
	author = {Sharpe, A. H. and Gaulton,G.N. and Ertl, H C and Finberg, R W and McDade, K K and Fields, B N and Greene, M I}
}
@article {543201,
	title = {Pathogenesis of viral infections. Basic concepts derived from the reovirus model.},
	journal = {N Engl J Med},
	volume = {312},
	number = {8},
	year = {1985},
	month = {1985 Feb 21},
	pages = {486-97},
	keywords = {Animals, Antibody Formation, Antigens, Viral, Cell Transformation, Viral, Immunity, Cellular, Mammalian orthoreovirus 3, Mice, Models, Biological, Receptors, Virus, Reoviridae, Reoviridae Infections, RNA, Viral, Virus Diseases, Virus Replication},
	issn = {0028-4793},
	doi = {10.1056/NEJM198502213120806},
	author = {Sharpe, A. H. and Fields, B N}
}
@article {543206,
	title = {Syngeneic monoclonal antiidiotype can induce cellular immunity to reovirus.},
	journal = {J Exp Med},
	volume = {160},
	number = {4},
	year = {1984},
	month = {1984 Oct 1},
	pages = {1195-205},
	abstract = {A syngeneic monoclonal antiidiotypic antibody was generated in BALB/c mice after repeated immunization with a BALB/c monoclonal anti-reovirus hemagglutinin (HA) antibody. The resultant syngeneic monoclonal antiidiotypic antibody, in the absence of adjuvant, was found to be capable of priming both BALB/c (H-2d, Igh-1a) and C3H/Hej (H-2k, Igh-1j) mice for Lyt-1+- and Lyt-2+-dependent responses against the mammalian reovirus. By the use of intertypic reassortants and variant virus analysis, the specificity of the response was finely mapped to the neutralization domain of the viral hemagglutinin (HA). Using purified monoclonal antiidiotype, we were able to compare the potency of antiidiotype to virus in terms of induction of immunity. 8 X 10(8) protein molecules were able to prime for cellular responses to reovirus. These studies indicate that in the reovirus system, T cells and B cells share idiotypic configurations, and that antiidiotypic antibodies of the type described herein may be useful in the development of vaccines against certain viral infections.},
	keywords = {Animals, Antibodies, Anti-Idiotypic, Antibodies, Monoclonal, Female, Hybridomas, Hypersensitivity, Delayed, Immunity, Cellular, Immunization, Passive, Immunoglobulin Allotypes, Immunoglobulin Idiotypes, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Neutralization Tests, Reoviridae, T-Lymphocytes, Cytotoxic, Thymus Gland},
	issn = {0022-1007},
	author = {Sharpe, A. H. and Gaulton,G.N. and McDade, K K and Fields, B N and Greene, M I}
}
@article {543216,
	title = {The interaction of mammalian reoviruses with the cytoskeleton of monkey kidney CV-1 cells.},
	journal = {Virology},
	volume = {120},
	number = {2},
	year = {1982},
	month = {1982 Jul 30},
	pages = {399-411},
	keywords = {Animals, Antigens, Viral, Cells, Cultured, Cercopithecus aethiops, Cytoskeleton, Inclusion Bodies, Viral, Kidney, Mammalian orthoreovirus 3, Microtubules, Mitochondria, Muscle Proteins, Reoviridae, Vimentin, Virus Replication},
	issn = {0042-6822},
	author = {Sharpe, A. H. and Chen, L B and Fields, B N}
}
@article {543211,
	title = {Reovirus inhibition of cellular RNA and protein synthesis: role of the S4 gene.},
	journal = {Virology},
	volume = {122},
	number = {2},
	year = {1982},
	month = {1982 Oct 30},
	pages = {381-91},
	keywords = {Animals, Genes, Viral, L Cells (Cell Line), Mammalian orthoreovirus 3, Methionine, Mice, Protein Biosynthesis, Recombination, Genetic, Reoviridae, RNA, RNA, Double-Stranded, RNA, Viral},
	issn = {0042-6822},
	author = {Sharpe, A. H. and Fields, B N}
}
@article {543226,
	title = {Intestinal M cells: a pathway for entry of reovirus into the host.},
	journal = {Science},
	volume = {212},
	number = {4493},
	year = {1981},
	month = {1981 Apr 24},
	pages = {471-2},
	abstract = {Thirty minutes after inoculation of reovirus type 1 into the intestinal lumen of the mouse, viruses were found adhering to the surface of intestinal M cells but not other epithelial cells. Within 1 hour, viruses were seen in the M cell cytoplasm and were associated with mononuclear cells in the intercellular space adjacent to the M cell. These findings suggest that M cells are the site where reovirus penetrates the intestinal epithelium.},
	keywords = {Animals, Animals, Suckling, Endocytosis, Extracellular Space, Intestinal Mucosa, Mice, Peyer{\textquoteright}s Patches, Receptors, Virus, Reoviridae, Reoviridae Infections},
	issn = {0036-8075},
	author = {Wolf, J L and Rubin, D H and Finberg, R and Kauffman, R S and Sharpe, A. H. and Trier, J S and Fields, B N}
}
@article {543231,
	title = {Reovirus inhibition of cellular DNA synthesis: role of the S1 gene.},
	journal = {J Virol},
	volume = {38},
	number = {1},
	year = {1981},
	month = {1981 Apr},
	pages = {389-92},
	abstract = {Type 3 reovirus inhibits L cell DNA synthesis, whereas type 1 reovirus exerts little or no effect on L cell DNA synthesis. By using recombinant viruses containing both type 1 and type 3 double-standard RNA segments, we determined that one double-stranded RNA segment, the reovirus type 3 S1 double-stranded RNA segment which encodes the viral hemagglutinin, segregates with and is responsible for the capacity of reovirus type 3 to inhibit L cell DNA synthesis.},
	keywords = {Animals, Cell Transformation, Viral, DNA, Genes, Viral, L Cells (Cell Line), Mice, Reoviridae, Ultraviolet Rays},
	issn = {0022-538X},
	author = {Sharpe, A. H. and Fields, B N}
}
@article {543221,
	title = {Role of the host cell in persistent viral infection: coevolution of L cells and reovoirus during persistent infection.},
	journal = {Cell},
	volume = {25},
	number = {2},
	year = {1981},
	month = {1981 Aug},
	pages = {325-32},
	abstract = {Mutant L cells, designated LR cells, were isolated after "curing" a persistently infected cell line (L/C) with antireovirus serum. The LR cells were shown to be virus-free; no reovirus was detectable by infectious center assays, plaque assays, presence of viral proteins, presence of viral dsRNA and immunofluorescence studies. Persistent infections were readily established n LR cells following infection with either cloned, low passage wild-type reovirus or cloned, low passage reovirus isolated from carrier cultures. Reovirus isolated from carrier cultures, however, grew much better than wild-type reovirus in LR cells and showed complete dominance over wild-type reovirus in coinfection experiments. Infection of LR cells with wild-type reovirus resulted in a low-level persistent infection with inefficient viral replication; these mutant L cells were partially resistant to infection with wild-type reovirus. In contrast, infection of the mutant L cells with virus isolated from the persistently infected cells resulted in a persistent infection accompanied with efficient viral replication. Infection of the original L cells with either wild-type reovirus or reovirus isolated from the persistently infected cells resulted in a lytic infection with no surviving cells. Thus the host cell plays a crucial role in the maintenance of persistent reovirus infection. Our results show that there is a coevolution of both mutant L cells and mutant reovirus during persistent infection.},
	keywords = {Animals, Clone Cells, Cytopathogenic Effect, Viral, L Cells (Cell Line), Mammalian orthoreovirus 3, Mice, Mutation, Reoviridae, Virus Replication},
	issn = {0092-8674},
	author = {Ahmed, R and Canning, W M and Kauffman, R S and Sharpe, A. H. and Hallum, J V and Fields, B N}
}
@article {543241,
	title = {The role of the reovirus hemagglutinin in viral virulence.},
	journal = {Ann N Y Acad Sci},
	volume = {354},
	year = {1980},
	month = {1980},
	pages = {125-34},
	keywords = {Animals, Antibodies, Viral, Ependyma, Genes, Viral, Hemagglutinins, Viral, Mammalian orthoreovirus 3, Mice, Microtubules, Neurons, Neutralization Tests, Recombination, Genetic, Reoviridae, T-Lymphocytes},
	issn = {0077-8923},
	author = {Fields, B N and Weiner, H. L. and Drayna, D T and Sharpe, A. H.}
}
@article {543236,
	title = {Specific disruption of vimentin filament organization in monkey kidney CV-1 cells by diphtheria toxin, exotoxin A, and cycloheximide.},
	journal = {Proc Natl Acad Sci U S A},
	volume = {77},
	number = {12},
	year = {1980},
	month = {1980 Dec},
	pages = {7267-71},
	abstract = {We have examined the effect of diphtheria toxin, Pseudomonas aeruginosa exotoxin A, and cycloheximide on the CV-1 cell cytoskeleton. Within a few hours after producing an inhibition of cellular protein synthesis, all these agents specifically disrupted the organization of the vimentin filament system with no discernable effect on microtubules or microfilaments during the period of observation. Furthermore, just as the inhibition of protein synthesis by cycloheximide is reversible, so was the disruption of vimentin filaments by cycloheximide.},
	keywords = {Animals, Bacterial Toxins, Cell Line, Cercopithecus aethiops, Cycloheximide, Cytoskeleton, Diphtheria Toxin, Exotoxins, Muscle Proteins, Pseudomonas aeruginosa, Vimentin},
	issn = {0027-8424},
	author = {Sharpe, A. H. and Chen, L B and Murphy, J R and Fields, B N}
}
@article {1051051,
	title = {[Determination of cholesterol and triglycerides in small volumes of blood serum]},
	journal = {Lab Delo},
	number = {4},
	year = {1979},
	month = {1979},
	pages = {244},
	keywords = {Cholesterol, Humans, Triglycerides},
	issn = {0023-6748},
	author = {Leonova, T Ia and Pressman, E K}
}
@article {1051361,
	title = {Plasma secretin concentrations in fasting and postprandial state in man},
	journal = {Am J Dig Dis},
	volume = {23},
	number = {11},
	year = {1978},
	month = {1978 Nov},
	pages = {981-8},
	abstract = {Plasma immunoreactive secretin concentrations were determined in both healthy subjects and patients with duodenal ulcer. The modified radioimmunoassay method could detect significant increases in the plasma secretin concentrations when 0.05 N HCl was infused intraduodenally at a rate of 1.1 and 2.2 ml/min. The mean fasting plasma secretin concentration of 13 normal healthy subjects was 4.4 +/- 0.38 pg/ml which was significantly less (P less than 0.01) than that of 13 duodenal ulcer patients, 6.9 +/- 0.64 pg/ml. In both groups ingestion of a meat-containing meal resulted in significant increase in the plasma secretin concentrations. Recording of pH from proximal duodenum indicated that pH fell periodically below 4.5 during the postprandial period, indicating that only a short segment of proximal duodenum was exposed to acid after meal. The postprandial rise in plasma secretin levels was abolished when antral pH was raised 5.5 by intragastric infusion of 0.3 N NaHCO3 solution. These observations indicate that although fasting plasma secretin levels are low, the plasma secretin levels increase significantly after ingestion of a meal. This increase appears to be attributable to an increased amount of acid delivered to the proximal duodenum, and patients with duodenal ulcer were found to release more secretin during the postprandial period than normal subjects.},
	keywords = {Adult, Duodenal Ulcer, Fasting, Female, Food, Gastric Acidity Determination, Humans, Hydrogen-Ion Concentration, Male, Middle Aged, Radioimmunoassay, Secretin, Time Factors},
	issn = {0002-9211},
	author = {Chey, W Y and Lee, Y H and Hendricks, J G and Rhodes, R A and Tai, H H}
}
@article {543261,
	title = {A genetic map of reovirus. 1. Correlation of genome RNAs between serotypes 1, 2, and 3.},
	journal = {Virology},
	volume = {84},
	number = {1},
	year = {1978},
	month = {1978 Jan},
	pages = {63-74},
	keywords = {Acetates, Chromosome Mapping, Crosses, Genetic, Cytoplasm, Electrophoresis, Polyacrylamide Gel, Genes, Viral, Glycine, Recombination, Genetic, Reoviridae, RNA, Viral, Serotyping, Species Specificity, Tromethamine, Virion},
	issn = {0042-6822},
	author = {Sharpe, A. H. and Ramig, R F and Mustoe, T A and Fields, B N}
}
@article {543256,
	title = {A genetic map of reovirus. II. Assignment of the double-stranded RNA-negative mutant groups C, D, and E to genome segments.},
	journal = {Virology},
	volume = {85},
	number = {2},
	year = {1978},
	month = {1978 Apr},
	pages = {531-4},
	keywords = {Crosses, Genetic, Genes, Viral, Mutation, Recombination, Genetic, Reoviridae, RNA, Viral, Temperature, Viral Plaque Assay},
	issn = {0042-6822},
	author = {Ramig, R F and Mustoe, T A and Sharpe, A. H. and Fields, B N}
}
@article {543251,
	title = {A genetic map of reovirus. III. Assignment of the double-stranded RNA-positive mutant groups A, B, and G to genome segments.},
	journal = {Virology},
	volume = {85},
	number = {2},
	year = {1978},
	month = {1978 Apr},
	pages = {545-56},
	keywords = {Crosses, Genetic, Genes, Viral, Mammalian orthoreovirus 3, Mutation, Recombination, Genetic, Reoviridae, RNA, Viral, Temperature},
	issn = {0042-6822},
	author = {Mustoe, T A and Ramig, R F and Sharpe, A. H. and Fields, B N}
}
@article {543246,
	title = {Genetics of reovirus: identification of the ds RNA segments encoding the polypeptides of the mu and sigma size classes.},
	journal = {Virology},
	volume = {89},
	number = {2},
	year = {1978},
	month = {1978 Sep},
	pages = {594-604},
	keywords = {Genetic Code, Peptides, Reoviridae, RNA, Messenger, RNA, Viral, Viral Proteins},
	issn = {0042-6822},
	author = {Mustoe, T A and Ramig, R F and Sharpe, A. H. and Fields, B N}
}
@article {1051396,
	title = {6-Phosphogluconate/glucose-6-phosphate ratio in rat pancreatic islets during inhibition of insulin release by exogenous insulin},
	journal = {Diabetes},
	volume = {26},
	number = {9},
	year = {1977},
	month = {1977 Sep},
	pages = {857-63},
	abstract = {Inhibition of glucose-stimulated insulin release by exogenous insulin has been demonstrated in pancreatic islets to be associated with a decrease of the NADPH/NADP ratio and the pentose-phosphate cycle activity. Batches of five islets were incubated for 15 and 90 minutes in 1 ml. of KRB buffer with 2 per cent albumin containing 3 mg./ml. glucose and 0, 200, 400, or 800 microU./ml. of rat insulin, and the glucose-6-phosphate (G6P) and 6-phosphogluconate (6PG) contents were determined by enzymatic cycling. In response to a rise in the concentration of insulin, the 6PG/G6P ratio decreased. A close relationship was observed between this decrease of 6PG/G6P ratio and the net insulin release, the absolute rate of glucose oxidation via the pentose phosphate cycle, and the NADPH/NADP ratios measured under similar conditions. The results suggest that exogenous insulin, directly or indirectly, regulates the pentose cycle activity in the pancreatic islets at the G6P dehydrogenase step.},
	keywords = {Animals, Carbon Dioxide, Female, Gluconates, Glucose, Glucosephosphates, Insulin, Islets of Langerhans, Kinetics, Male, NAD, NADP, Oxidation-Reduction, Pentosephosphates, Rats},
	issn = {0012-1797},
	author = {Akhtar, M S and Verspohl, E and Hegner, D and Ammon, H P}
}
@article {1051356,
	title = {Anomalies in some properties of powder mixtures},
	journal = {J Pharm Pharmacol},
	volume = {28},
	number = {5},
	year = {1976},
	month = {1976 May},
	pages = {415-9},
	abstract = {Mixtures of lactose and paracetamol and of lactose and oxytetracycline exhibit anomalous properties. The mean particle sizes, tensile strengths and flow properties of the mixtures are not proportionally intermediate between those of the constituents. The results are ascribed to changes that occur in the packing arrangements of the particles. These changes could have practical consequences in monitoring the progress of a mixing operation by measuring apparent particle size and in controlling the properties of granules, capsules and tablets prepared from the mixtures.},
	keywords = {Acetaminophen, Drug Compounding, Excipients, Lactose, Oxytetracycline, Particle Size, Powders},
	issn = {0022-3573},
	author = {Varthalis, S and Pilpel, N}
}
@article {1051311,
	title = {Kinetics of the antibody response to type III pneumococcal polysaccharide. II. Factors influencing the serum antibody levels after immunization with an optimally immunogenic dose of antigen},
	journal = {J Immunol},
	volume = {116},
	number = {1},
	year = {1976},
	month = {1976 Jan},
	pages = {52-64},
	abstract = {When the number of PFC present in the spleen was measured at 24-hr intervals after immunizing with an optimally immunogenic dose of type III pneumococcal polysaccharide (SSS-III), maximal numbers of PFC were attained 4 days after immunization; thereafter, the number of PFC decreased rapidly. By contrast, serum antibody levels, which were measured in the same mice using a Farr test, reached peak values 5 days after immunization and then declined much more slowly than did the number of PFC. Two factors were found to contribute to this disparity. First, experiments conducted with splenectomized mice showed that extrasplenic antibody synthesis, which began between days 3 and 4 after immunization and peaked on days 6 to 7, accounted for nearly one-third of the total amount of serum antibody produced. Second, the average rate of antibody synthesis by PFC increased through day 6 after immunization and then declined. Antigen-antibody dissociation tests showed that the avidity of the serum antibody obtained 4 to 7 days after immunization was the same. Moreover, during the same interval, all the antibody detected by the Farr test was of the IgM class. Thus, a change in avidity or class of immunoglobulin after day 5 did not account for the disparity observed. The clearance rate of antibody injected i.v. into nonimmune and immunized mice was studied. The data obtained indicated that accelerated clearance of antibody was occurring prior to day 3 after immunization; however, after day 3 the antibody clearance rate was constant and was the same as that found when antibody was injected into nonimmune mice. These findings affirmed the results of previous studies showing that treadmill neutralization was not important in determining the serum antibody levels present after immunization with an optimally immunogenic dose of SSS-III.},
	keywords = {Animals, Antibodies, Bacterial, Antibody Formation, Antibody Specificity, Female, Hemolytic Plaque Technique, Immunization, Immunization, Passive, Immunoglobulin A, Immunoglobulin G, Immunoglobulin M, Kinetics, Mice, Mice, Inbred BALB C, Polysaccharides, Bacterial, Spleen, Splenectomy, Streptococcus pneumoniae, Time Factors},
	issn = {0022-1767},
	author = {Jones, J M and Amsbaugh, D F and Prescott, B}
}
@article {1051261,
	title = {Identification of cariogenic bacteria by fluorescent antibody and other techniques: an international symposium. New York City, April 3-4, 1975. Concluding remarks: the current status of the National Caries Program},
	journal = {J Dent Res},
	volume = {55},
	year = {1976},
	month = {1976 Jan},
	pages = {A207-9},
	keywords = {Bacteria, Congresses as Topic, Dental Caries, Fluorescent Antibody Technique, Humans, National Institutes of Health (U.S.), New York City, United States},
	issn = {0022-0345},
	author = {O{\textquoteright}Brien, T C}
}
@article {1051266,
	title = {Schizophrenic inability to disattend from strong aspects of meaning},
	journal = {J Abnorm Psychol},
	volume = {85},
	number = {1},
	year = {1976},
	month = {1976 Feb},
	pages = {35-40},
	keywords = {Adult, Antipsychotic Agents, Chronic Disease, Humans, Schizophrenia, Schizophrenic Language, Schizophrenic Psychology, Semantics},
	issn = {0021-843X},
	author = {Chapman, L J and Chapman, J P and Daut, R L}
}
@article {1051291,
	title = {Stages of bone marrow transplantation: a psychiatric perspective},
	journal = {Psychosom Med},
	volume = {38},
	number = {6},
	year = {1976},
	month = {1976 Nov-Dec},
	pages = {439-46},
	abstract = {Patients undergoing bone marrow transplantation were closely followed by a psychiatric service functioning as part of a multidisciplinary team. A somewhat predictable pattern of psychological reactions to the stress of various stages of the procedure appeared to emerge. Approaches to patient evaluation, typical patient responses, and suggestions for working with these patients and their families are described.},
	keywords = {Adaptation, Psychological, Affective Symptoms, Anemia, Aplastic, Bone Marrow Cells, Bone Marrow Transplantation, Defense Mechanisms, Graft Rejection, Graft vs Host Reaction, Humans, Immunosuppression, Informed Consent, Leukemia, Patient Care Planning, Patient Isolation, Personality, Stress, Psychological},
	issn = {0033-3174},
	author = {Brown, H N and Kelly, M J}
}
@article {1051256,
	title = {Effects of reducing and oxidizing agents on the adenylate cyclase activity in adipocyte plasma membranes},
	journal = {FEBS Lett},
	volume = {65},
	number = {1},
	year = {1976},
	month = {1976 May 15},
	pages = {96-8},
	keywords = {Adenylyl Cyclases, Adipose Tissue, Adrenocorticotropic Hormone, Animals, Cell Membrane, Enzyme Activation, Epididymis, Ferricyanides, Male, NAD, NADP, Norepinephrine, Oxidation-Reduction, Rats},
	issn = {0014-5793},
	author = {L{\"o}w, H and Werner, S}
}
@article {1051191,
	title = {The specificity of heterophil antibodies in patients and healthy donors with no or minimal signs of infectious mononucleosis},
	journal = {Blood},
	volume = {47},
	number = {1},
	year = {1976},
	month = {1976 Jan},
	pages = {91-8},
	abstract = {Over several years sera were collected from 14 heterophil-positive students or patients who did not fulfill minimal hematologic criteria for infectious mononucleosis (I.M.) The specificity of these heterophil reactions for I.M. was investigated by determining antibodies to Epstein-Barr virus-determined antigens, i.e., to viral capsid antigens (VCA), early antigens (EA), and EBV-associated nuclear antigens (EBNA). On the basis of detectable anti-EA and/or the early absence and late emergence of anti-EBNA, four of these 14 individuals showed evidence of a current or very recent primary Epstein-Barr virus infection. The other ten patients showed antibody patterns indicative of Epstein-Barr virus infections in the past, and no firm conclusions could be drawn with regard to the specificity of their heterophil reactions. It was assumed, however, that some represented atypical clinical forms of EBV infection and that timing of specimen collection was a factor in explaining the paucity of Downey cells. In three patients, the absorbed heterophil-positive reactions persisted with little change in titer for at least 22 mo and thus might represent false-positive tests.},
	keywords = {Adolescent, Adult, Agglutinins, Antibodies, Heterophile, Antigens, Aspartate Aminotransferases, Capsid, Female, gamma-Glutamyltransferase, Herpesvirus 4, Human, Humans, Infectious Mononucleosis, Male, Serologic Tests},
	issn = {0006-4971},
	author = {Horwitz, C A and Henle, W and Henle, G and Polesky, H and Wexler, H and Ward, P}
}
@article {1051101,
	title = {Metabolism of dihalomethanes to formaldehyde and inorganic halide. I. In vitro studies},
	journal = {Drug Metab Dispos},
	volume = {4},
	number = {4},
	year = {1976},
	month = {1976 Jul-Aug},
	pages = {357-61},
	abstract = {Metabolism of dihalomethanes by rat liver cytosol fractions yielded formaldehyde and inorganic halide as products. Loss of metabolic activity resulting from dialysis of the cytosol was restored with glutathione. Cysteine could not substitute for GSH. No other cofactor was found to be required for activity. The optimum conditions for this biotransformation with respect to time, temperature, protein concentration, and pH were determined. Rates of metabolism of dihalomethanes showed the following order: CH2i2 greater than CH2Br2 congruent to CH2BrCi greater than CH2Ci2. Administration of the enzyme inducer, phenobarbital, to rats did not alter this metabolic pathway nor did repeated administration of CH2Br2 or CH2Ci2 change the rate of metabolism. The enzyme catalyzing this reaction was localized in the liver. Compounds known to serve as substrates for various GSH transferases inhibited the reaction as did those capable of interacting with sulfhydryl groups.},
	keywords = {Anaerobiosis, Animals, Brain, Bromides, Chlorides, Cysteine, Cytosol, Formaldehyde, Glutathione, Hydrocarbons, Halogenated, Iodides, Kinetics, Liver, Methane, Organ Specificity, Rats},
	issn = {0090-9556},
	author = {Ahmed, A E and Anders, M W}
}
@article {1051091,
	title = {Quantitative fractionation of alkaline phosphatase isoenzymes according to their thermostability},
	journal = {Clin Chem},
	volume = {22},
	number = {1},
	year = {1976},
	month = {1976 Jan},
	pages = {42-8},
	abstract = {Continuous monitoring of heat denaturation of a mixture of alkaline phosphatase isoenzymes at 60 degrees C and pH 7.5 permits the simultaneous direct identification and quantitation of three isoenzymes: the placental isoenzyme, the L-phenylalanine-sensitive intestinal isoenzyme, and the liver isoenzyme (hepatocytic). The isoenzyme that is principally of bone origin cannot be identified as such without the help of other diagnostic aids and the patient{\textquoteright}s medical history. All human tissues contain alkaline phosphatase, many organs more than one of the isoenzymes. Liver alkaline phosphatase, which constitutes 40-50\% of normal serum alkaline phosphatase activity, was measured in the serum of persons with various liver diseases. Its activity exceeded normal in all types of liver disease; in 80\% of cases this increase was accompanied by increased gamma-glutamyl-transferase activity, but the quantitative correlationship (r = 0.54) was not as good as expected if both enzymes come from the same source and are indices of liver dieases. Liver alkaline phosphatase activity increases in the blood early in liver disease, before most liver tests show abnormalities. The other major isoenzyme of normal serum probably represents a mixture of isoenzymes from bone and reticulo-endothelial and vascular tissues, which all contain the same "very heat-labile" alkaline phosphatase. Cord blood and children{\textquoteright}s sera contain mostly this very heat-labile isoenzyme.},
	keywords = {Alkaline Phosphatase, Blood, Bone and Bones, Duodenum, Female, gamma-Glutamyltransferase, Humans, Hydrogen-Ion Concentration, Isoenzymes, Liver, Liver Diseases, Male, Phosphates, Placenta, Pregnancy, Protein Denaturation, Temperature},
	issn = {0009-9147},
	author = {PetitClerc, C}
}
@article {1051011,
	title = {Microcalorimetric study of the anaerobic growth of Escherichia coli: growth thermograms in a synthetic medium},
	journal = {J Bacteriol},
	volume = {125},
	number = {1},
	year = {1976},
	month = {1976 Jan},
	pages = {14-8},
	abstract = {A microcalorimetric technique was used for studying the growth of Escherichia coli during anaerobiosis. The growth thermograms obtained are complex and the shape of curves is dependent on the hydrogen lyase activity of the cells. Fermentation balances are given for different culture conditions, and simple growth thermograms are obtained when the hydrogen lyase activity is inhibitied.},
	keywords = {Acetates, Anaerobiosis, Calorimetry, Escherichia coli, Ethanol, Fermentation, Formates, Glucose, Hydrogen, Hydrogen-Ion Concentration, Lactates, Oxidoreductases, Succinates},
	issn = {0021-9193},
	author = {Belaich, A and Belaich, J P}
}
@article {1051006,
	title = {Radiation lethality in the opossum},
	journal = {Radiat Res},
	volume = {68},
	number = {3},
	year = {1976},
	month = {1976 Dec},
	pages = {514-7},
	keywords = {Animals, Cobalt Radioisotopes, Dose-Response Relationship, Radiation, Gamma Rays, Male, Opossums, Radiation Injuries, Experimental},
	issn = {0033-7587},
	author = {Prasad, N and Bushong, S C and North, L B and Thornby, J}
}
@article {702866,
	title = {Complete enzymic digestion of acidic proteins.},
	journal = {Int J Pept Protein Res},
	volume = {8},
	number = {4},
	year = {1976},
	month = {1976},
	pages = {379-83},
	abstract = {Acidic proteins are usually resistant to complete enzymic hydrolysis. The increasing number of "unusual" amino acids, which are unstable to acid hydrolysis, makes it necessary to have a method of enzymic hydrolysis applicable to all proteins. The complete hydrolysis of four acidic proteins by subtilisin plus leucine amino-peptidase plus prolidase followed by carboxypeptidase C, is described. Recoveries of amino acids were in excellent agreement with the expected content from the known sequences.},
	keywords = {Amino Acids, Carboxypeptidases, Dipeptidases, Fibrinogen, Gastrins, Hydrogen-Ion Concentration, Hydrolysis, Leucyl Aminopeptidase, Pepsinogens, Ribonucleases, Subtilisins},
	issn = {0367-8377},
	author = {Kay, J}
}
@article {702856,
	title = {Letter: Protostreptovaricins I-V.},
	journal = {J Am Chem Soc},
	volume = {98},
	number = {3},
	year = {1976},
	month = {1976 Feb 4},
	pages = {870-2},
	keywords = {Chemical Phenomena, Chemistry, Chromatography, Magnetic Resonance Spectroscopy, Streptovaricin},
	issn = {0002-7863},
	author = {Deshmukh, P V and Kakinuma, K and Ameel, J J and Rinehart, K L and Wiley, P F and Li, L H}
}
@article {702861,
	title = {[Transport of a cardiac patient].},
	journal = {Ann Anesthesiol Fr},
	volume = {17},
	number = {5},
	year = {1976},
	month = {1976},
	pages = {599-601},
	keywords = {Emergency Service, Hospital, Female, Humans, Middle Aged, Shock, Cardiogenic, Tachycardia, Transportation of Patients},
	issn = {0003-4061},
	author = {Guyot, J M and Duchevet, G}
}
@article {1051411,
	title = {Bovine liver dihydrofolate reductase: purification and properties of the enzyme},
	journal = {Biochemistry},
	volume = {14},
	number = {24},
	year = {1975},
	month = {1975 Dec 02},
	pages = {5261-7},
	abstract = {A purification procedure is reported for obtaining bovine liver dihydrofolate reductase in high yield and amounts of 100-200 mg. A key step in the procedure is the use of an affinity gel prepared by coupling pteroyl-L-lysine to Sepharose. The purified reductase has a specific activity of about 100 units/mg and is homogeneous as judged by analytical ultracentrifugation, polyacrylamide gel electrophoresis, and titration with methotrexate. The products of the first step of Edman degradation indicated a minimum purity of 79\%. The reductase has a molecular weight of about 21500 on the basis of amino acid composition and 22100 +/- 300 from equilibrium sedimentation. It is not inhibited by antiserum to the Streptococcus faecium reductase (isoenzyme 2). Unlike the reductase of many other vertebrate tissues, the bovine enzyme is inhibited by mercurials rather than activated and it has a single pH optimum at both low and high ionic strength. However, the position of the pH optimum is shifted and the activity increased by increasing ionic strength. Automatic Edman degradation has been used to determine 34 of the amino-terminal 37 amino acid residues. Considerable homology exists between this region and the corresponding regions of the reductase from S. faecium and from Escherichia coli. This strengthens the idea that this region contributes to the structure of the binding site for dihydrofolate.},
	keywords = {Amino Acid Sequence, Amino Acids, Animals, Antigen-Antibody Reactions, Cattle, Chromatography, Affinity, Hydrogen-Ion Concentration, Isoenzymes, Kinetics, Liver, Methotrexate, Tetrahydrofolate Dehydrogenase},
	issn = {0006-2960},
	author = {Peterson, D L and Gleisner, J M and Blakley, R L}
}
@article {1051416,
	title = {Phenomenon of hot-cold hemolysis: chelator-induced lysis of sphingomyelinase-treated erythrocytes},
	journal = {Infect Immun},
	volume = {12},
	number = {5},
	year = {1975},
	month = {1975 Nov},
	pages = {1104-11},
	abstract = {Staphylococcus aureus produces a phospholipase C specific for sphingomyelin (beta-hemolysin). Erythrocytes with approximately 50\% sphingomyelin in their membranes, e.g., from sheep, have been shown to have up to 60\% of this phospholipid hydrolyzed by this enzyme at 37 C in isotonic buffered saline without hemolysis. Cooling of sphingomyelinase C-treated erythrocytes to 4 C causes complete lysis of the cells, a phenomenon known as hot-cold hemolysis. The addition of ethylenediaminetetraacetate (EDTA) to sheep erythrocytes preincubated with sphingomyelinase C was found to induce rapid hemolysis at 37 C. The treated cells became susceptible to chelator-induced hemolysis and to hot-cold hemolysis simultaneously, and the degree of lysis of both mechanisms increased equally with prolonged preincubation with sphingomyelinase C. Erythrocytes of species not readily susceptible to hot-cold hemolysis were equally insusceptible to chelator-induced lysis. Chelators of the EDTA series were the most effective, whereas chelators more specific for Ca2+, Zn2+, Fe2+, Cu2+, and Mg2+ were without effect. The rate of chelator-induced lysis was dependent on the preincubation period with beta-hemolysin and on the concentration of chelator added. The optimal concentration of EDTA was found to equal the amount of exogenously added Mg2+, a cation necessary for sphingomyelinase C activity. Hypotonicity increased the rate of chelator-induced hemolysis, whereas increasing the osmotic pressure to twice isotonic completely inhibited chelator-induced lysis. The data suggest that exogenously added and/or membrane-bound divalent cations are important for the stability of sphingomyelin-depleted membranes. The phenomenon of hot-cold hemolysis may be a consequence of the temperature dependence of divalent ion stabilization.},
	keywords = {2,2{\textquoteright}-Dipyridyl, Animals, Chelating Agents, Edetic Acid, Erythrocytes, Hemolysin Proteins, Hemolysis, Humans, Osmolar Concentration, Pentetic Acid, Phenanthrolines, Phosphoric Diester Hydrolases, Rabbits, Sheep, Spectrophotometry, Sphingomyelin Phosphodiesterase, Temperature, Time Factors},
	issn = {0019-9567},
	author = {Smyth, C J and M{\"o}llby, R and Wadstr{\"o}m, T}
}
@article {1051366,
	title = {Determinants of intracellular pH in the erythrocyte},
	journal = {Br J Haematol},
	volume = {29},
	number = {3},
	year = {1975},
	month = {1975 Mar},
	pages = {369-72},
	keywords = {Cell Membrane Permeability, Diphosphoglyceric Acids, Erythrocytes, Humans, Hydrogen-Ion Concentration, Membrane Potentials},
	issn = {0007-1048},
	author = {Warth, J and Desforges, J F}
}
@article {1051391,
	title = {Methods to improve detection of pneumococci in respiratory secretions},
	journal = {J Clin Microbiol},
	volume = {2},
	number = {5},
	year = {1975},
	month = {1975 Nov},
	pages = {453-5},
	abstract = {Simple methods to enhance the detection of pneumococci in respiratory secretions are needed. Sheep blood agar containing 5 mug of gentamicin per ml was more often positive (89\%) than either standard sheep blood agar (54\%) or mouse inoculation (65\%) in recovering pneumococci from 62 adult and pediatric patients. In adults, the direct quellung test on sputum smear was a rapid, sensitive method for predicting subsequent pneumococcal isolation by culture (19 of 20 patients, 95\%). The quellung test and gentamicin plate show improved sensitivity over current techniques for pneumococcal detection and can be recommended for general use.},
	keywords = {Adult, Agar, Animals, Bacteriological Techniques, Blood, Child, Child, Preschool, Evaluation Studies as Topic, Gentamicins, Humans, Pharynx, Sheep, Sputum, Streptococcus pneumoniae},
	issn = {0095-1137},
	author = {Dilworth, J A and Stewart, P and Gwaltney, J M and Hendley, J O and Sande, M A}
}
@article {1051381,
	title = {Multiple cyclic nucleotide phosphodiesterases in rat kidney},
	journal = {Kidney Int},
	volume = {8},
	number = {5},
	year = {1975},
	month = {1975 Nov},
	pages = {284-91},
	abstract = {Using DEAE-cellulose chromatography and Agarose gel filtration we have partially purified a low Km cyclic adenosine monophosphate (AMP) phosphodiesterase from the 100,000 X g supernatant of rat kidneys. The characteristics of this enzyme included a Km of approximately 4 muM a pH optimum of around 8.0 and a requirement for magnesium. This preparation should be suitable for investigation of possible effects of hormones, drugs and cellular constituents on the cyclic AMP pathway through any direct effects on the low Km enzyme. We have also demonstrated a nonspecific, high Km cyclic nucleotide phosphodiesterase and possibly a specific cyclic guanosine monophosphate (GMP) phosphodiesterase in the soluble fraction from rat kidneys.},
	keywords = {3{\textquoteright},5{\textquoteright}-Cyclic-AMP Phosphodiesterases, Animals, Chromatography, DEAE-Cellulose, Chromatography, Gel, Chromatography, Ion Exchange, Cyclic AMP, Cyclic GMP, Hydrogen-Ion Concentration, Kidney, Phosphoric Diester Hydrolases, Rats},
	issn = {0085-2538},
	author = {Gulyassy, P F and Farrand, J R and Gugler, H D}
}
@article {1051386,
	title = {Simultaneous determination of propranolol and 4-hydroxypropranolol in plasma by mass fragmentography},
	journal = {J Chromatogr},
	volume = {114},
	number = {2},
	year = {1975},
	month = {1975 Nov 26},
	pages = {351-9},
	abstract = {A quantitative method for the simultaneous determination of propranolol and its active metabolite 4-hydroxypropranolol in human plasma is described. Plasma samples are extracted at pH 9.6 with ethyl acetate after the addition of sodium bisulphite and the internal standard oxprenolol. The extracts are derivatized with trifluoroacetic anhydride before separation on a gas chromatograph--mass spectrometer. Detection and quantitation of the trifluoroacetyl derivatives are made by single-ion monitoring. The minimum detectable concentration of propranolol is 1 ng/ml and of 4-hydroxypropranolol 5 ng/ml using 1-ml plasma samples. No interferences from normal plasma constituents or from drugs commonly prescribed together with propranolol were detected.},
	keywords = {Chromatography, Gas, Gas Chromatography-Mass Spectrometry, Hydrogen-Ion Concentration, Methods, Propranolol},
	author = {Walle, T and Morrison, J and Walle, K and Conradi, E}
}
@article {1051341,
	title = {Antagonistic relationships between electron transport and P700 in chloroplasts and intact algae},
	journal = {Z Naturforsch C},
	volume = {30},
	number = {6},
	year = {1975},
	month = {1975 Nov-Dec},
	pages = {761-70},
	abstract = {The effects of divalent salts and 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU) upon nicotinamide adenine dinucleotide phosphate (NADP) reduction and P700 in isolated chloroplasts are described and compared with the influence of DCMU on oxygen evolution and P700 in intact cells. Most experiments were carried out with a steady-state relaxation spectrometer. A kinetic mechanism for the estimation of P700 fluxes is proposed and experimentally tested. Good agreement between theory and experiment was found. Concurrent measurements of P700 and NADP reduction revealed two antagonisms: addition of divalent cations caused an increase in the yield of NADP reduction and a decrease in the yield of P700. Conversely, in the presence of Mg2+ low concentrations of DCMU decreased the yield of NADP reduction and increased the yield of P700. Aging of the chloroplasts at 30 degrees C exerted a similar effect. With far-red actinic light, Mg2+ stimulated the yield of NADP reduction without affecting the flux. Also, in the absence of Mg2+, DCMU inhibited both reactions although P700 required a higher herbicide concentration for fractional inhibition than NADP reduction. In the presence of Mg2+, chloroplasts resembled intact algae in which a high rate of oxygen evolution was accompanied by little P700 turn-over. Titration with DCMU decreased the rate of photosynthesis and increased P700 flux. On the whole, the data suggest that P700 relaxing in 20 msec is not directly involved in linear electron transport.},
	keywords = {Chlorella, Chloroplasts, Cytochromes, Diuron, Electron Transport, Magnesium, Methylphenazonium Methosulfate, NADP, Oxygen Consumption, Plants},
	issn = {0341-0382},
	author = {Rurainski, H J}
}
@article {1051316,
	title = {Beef liver L-Glutamate dehydrogenase mechanism: presteady state study of the catalytic reduction of 2.oxoglutarate by NADPH},
	journal = {Biochem Biophys Res Commun},
	volume = {67},
	number = {4},
	year = {1975},
	month = {1975 Dec 15},
	pages = {1527-36},
	keywords = {Animals, Cattle, Glutamate Dehydrogenase, Ketoglutaric Acids, Kinetics, Liver, NADP, Oxidation-Reduction, Spectrometry, Fluorescence, Spectrophotometry, Ultraviolet},
	issn = {0006-291X},
	author = {Jallon, J M and Risler, Y and Iwatsubo, M}
}
@article {1051326,
	title = {Monoanion inhibition and 35Cl nuclear magnetic resonance studies of renal dipeptidase},
	journal = {Biochemistry},
	volume = {14},
	number = {24},
	year = {1975},
	month = {1975 Dec 02},
	pages = {5280-5},
	abstract = {Kinetic analyses of monoanion inhibition and 15Cl nuclear magnetic resonance at 5.88 MHz were employed to study monoanion interactions with the zinc metalloenzyme, renal dipeptidase. The enzyme-catalyzed hydrolysis of glycyldehydrophenylalanine exhibited competitive inhibition when the reaction rate was determined in the presence of the monovalent anions fluoride, chloride, bromide, iodide, azide, nitrate, or thiocyanate or upon the addition of the divalent anion, sulfate. Competitive inhibition was produced by these anions. One anion was bound per enzyme molecule, and except in the case of fluoride all of the anions appeared to bind at the same site. Cyanide ion produced a much more effective inhibition of renal dipeptidase than the other monoanions, and it was shown that two cyanide ions were bound per enzyme molecule. An investigation of the effect of pH upon monoanion inhibition suggested that the anion inhibitors bind to the group with a pK of approximately 7.8. Complete dissociation of this group (approximately pH 8.4) eliminates the inhibitory effect of anions. The 35Cl line broadening produced by renal dipeptidase in 0.5 M NaCl solutions was 100 times more effective than that produced by equivalent concentrations of aquozinc(II). The line broadening was dependent upon the concentration of the metalloenzyme and independent of the frequency of the exciting radiation. When zinc ion was removed from the metalloenzyme by dialysis or when chloride was titrated from the metalloenzyme by cyanide, line broadening was decreased. Treatment of renal dipeptidase with saturating concentrations of the competitive inhibitor, guanosine triphosphate, in the presence of 0.5 M NaCl also produced a significant decrease in the 35Cl line width. The 35Cl line broadening produced by renal dipeptidase was shown to decrease with increasing pH through the range pH 5.8-10.8. This line-width variation with pH appeared to result from the titration of a site on the metalloprotein with an approximate pK of 7.4. Temperature studies of 35Cl line broadening by the metalloenzyme in the presence of chloride and cyanide inhibitors suggest that the fast exchange process pertains and that the dominant relaxation mechanism is quadrupolar in nature.},
	keywords = {Animals, Anions, Azides, Bromides, Chlorides, Cyanides, Dipeptidases, Fluorides, Hydrogen-Ion Concentration, Iodides, Kidney Cortex, Kinetics, Magnetic Resonance Spectroscopy, Mathematics, Nitrates, Protein Conformation, Sulfates, Swine, Temperature, Thiocyanates},
	issn = {0006-2960},
	author = {Ferren, L G and Ward, R L and Campbell, B J}
}
@article {1051336,
	title = {[New values for the molar extinction coefficients of NADH and NADPH for the use in routine laboratories (author{\textquoteright}s transl)]},
	journal = {Z Klin Chem Klin Biochem},
	volume = {13},
	number = {11},
	year = {1975},
	month = {1975 Nov},
	pages = {507-8},
	abstract = {Extensive re-investigations with regard to the molar extinction coefficients of NADH and NADPH proved that in future, calculations in routine work can be performed with the following much more accurate epsilon-values: 6.15 x 10(3) 1 x mol-1 x cm-1 at Hg 334 nm (NADH and NADPH), 6.3 X 10(3) 1 X mol-1 x cm-1 at 340 nm (NADH and NADPH), 3.4 X 10(3) 1 X mol-1 X Cm-1 (NADH) and 3.5 x 10(3) 1 x mol-1 x cm-1 (NADPH) at Hg 365 nm, respectively. The safest measurement is performed at Hg 334 nm, because here epsilon is identical for both coenzymes and deviations of the epsilon-value caused by temperature, pH and ionic strength are less than 0.5\%.},
	keywords = {Colorimetry, Hydrogen-Ion Concentration, NAD, NADP, Quality Control, Temperature},
	issn = {0044-2933},
	author = {Bergmeyer, H U}
}
@article {1051331,
	title = {Practolol, caffeine and calcium in the regulation of mechanical activity of the cardiac ventricle in Myxine glutinosa (L.)},
	journal = {Comp Biochem Physiol C},
	volume = {52},
	number = {1},
	year = {1975},
	month = {1975 Oct 01},
	pages = {17-22},
	keywords = {Animals, Caffeine, Calcium, Dose-Response Relationship, Drug, Fishes, Hagfishes, Heart Ventricles, Hydroxydopamines, Myocardial Contraction, Phenoxybenzamine, Phentolamine, Practolol, Propranolol, Reserpine, Theophylline, Ventricular Function},
	issn = {0306-4492},
	author = {Storesund, A and Helle, K B}
}
@article {1051281,
	title = {[Bone marrow transplantation in patients with aplastic anemia]},
	journal = {Hamatol Bluttransfus},
	volume = {16},
	year = {1975},
	month = {1975},
	pages = {330-51},
	keywords = {Adolescent, Adult, Anemia, Aplastic, Bone Marrow Cells, Bone Marrow Transplantation, Child, Child, Preschool, Female, Graft vs Host Reaction, HLA Antigens, Humans, Male, Middle Aged, Tissue Donors, Transplantation, Homologous},
	issn = {0440-0607},
	author = {Dooren, L J and de Koning, J and Kamphuis, R P and Uittenbogaart, C H and Brubakk, A M and Vossen, J M}
}
@article {1051271,
	title = {Bone marrow transplants},
	journal = {Proc R Soc Med},
	volume = {68},
	number = {9},
	year = {1975},
	month = {1975 Sep},
	pages = {577-8},
	keywords = {Agammaglobulinemia, Bone Marrow Cells, Bone Marrow Transplantation, Female, Graft vs Host Reaction, Humans, Immunoglobulin A, Immunoglobulin G, Immunoglobulin M, Immunologic Deficiency Syndromes, Infant, Infant, Newborn, Male, Methotrexate, Transplantation, Homologous},
	issn = {0035-9157},
	author = {Anderson, I M}
}
@article {1051306,
	title = {The college health-practice preceptorship in the training of physician{\textquoteright}s assistants},
	journal = {J Am Coll Health Assoc},
	volume = {24},
	number = {2},
	year = {1975},
	month = {1975 Dec},
	pages = {98-9},
	keywords = {Physician Assistants, Preceptorship, Student Health Services, Wisconsin},
	issn = {0002-7944},
	author = {Johnson, D D}
}
@article {1051286,
	title = {[Intermediate plateaux in kinetics of the reaction catalyzed by biodegradative L-threonine dehydratase from Escherichia coli]},
	journal = {Biokhimiia},
	volume = {40},
	number = {3},
	year = {1975},
	month = {1975 May-Jun},
	pages = {645-51},
	abstract = {It has been shown that for the reaction catalyzed by "biodegradative" L-threonine dehydratase from E. coli strains K-12 and 980 in 0.5 M phosphate-carbonate buffer, pH 8.4 and pH 9.5, the plots of initial reaction rate (v) versus the initial substrate concentration ([S]0 are characterized by several inflection points, i. e. an intermediate plateau. The plot of v versus the allosteric activator (AMP) concentration have very complicated shapes: there are several inflection points, and also the maximum at L-threonine concentration equal to 3-10(2) and 5-10(-2) M. High AMP concentrations inhibit the enzyme at high substrate concentrations. The reduced glutathion dose not influence the enzyme and does not alter the activating effect of AMP. On the basis of the data obtained it is proposed that the substrate and AMP shift the equilibrium between multiple oligomeric enzyme forms differing in catalytic activity and kinetic manifestations of allosteric interactions between the active and allosteric AMP-binding sites towards polymerization. Thus, the functioning the enzyme under study is discussed in the frames of the model of dissociating regulatory enzymes with multiple intermediate oligomeric forms.},
	keywords = {Adenosine Monophosphate, Allosteric Regulation, Allosteric Site, Binding Sites, Escherichia coli, Hydro-Lyases, Hydrogen-Ion Concentration, Kinetics, Protein Binding, Threonine Dehydratase},
	issn = {0320-9725},
	author = {Sinelnikova, E M and Dvoretskova, T V and Kagan, Z S}
}
@article {1051211,
	title = {Coronary vascular and myocardial responses to carotid body stimulation in the dog},
	journal = {Am J Physiol},
	volume = {229},
	number = {3},
	year = {1975},
	month = {1975 Sep},
	pages = {754-60},
	abstract = {Coronary vascular and myocardial responses to selective hypoxic and/or hypercapnic carotid chemoreceptor stimulation were investigated in constantly ventilated, pentobarbital or urethan-chloralose anesthetized dogs. Bilaterally isolated carotid chemoreceptors were perfused with autologous blood of varying O2 and CO2 tensions via an extracorporeal lung circuit. Systemic gas tensions were unchanged. Effects of carotid chemoreceptor stimulation on coronary vascular resistance, left ventricular dP/dt, and strain-gauge arch output were studied at natural coronary blood flow with the chest closed and during constant-flow perfusion of the left common coronary artery with the chest open. Carotid chemoreceptor stimulation slightly increased left ventricular dP/dt and slightly decreased the strain-gauge arch output, while markedly increasing systemic pressure. Coronary blood flow increased; however, coronary vascular resistance wa.as not affected. These studies show that local carotid body stimulation increases coronary blood flow but has little effect on the myocardium. The increase in coronary blood flow results mainly from an increase in systemic arterial pressure. Thus these data provide little evidence for increased sympathetic activity of the heart during local stimulation of the carotid chemoreceptors with hypoxic and hypercapnic blood.},
	keywords = {Animals, Blood Pressure, Carbon Dioxide, Carotid Body, Carotid Sinus, Chemoreceptor Cells, Coronary Circulation, Dogs, Female, Heart, Heart Rate, Hydrogen-Ion Concentration, Male, Oxygen, Perfusion, Pressure, Vagotomy, Vascular Resistance, Ventricular Function},
	issn = {0002-9513},
	author = {Ehrhart, I C and Parker, P E and Weidner, W J and Dabney, J M and Scott, J B and Haddy, F J}
}
@article {1051226,
	title = {Frustration},
	journal = {Alumnae Mag Columbia Univ Presbyt Hosp Sch Nurs Alumnae Assoc},
	volume = {71},
	number = {2},
	year = {1975},
	month = {1975 Spring},
	pages = {11-2, 15},
	keywords = {Nursing, Patient Care Planning},
	issn = {0069-634X},
	author = {Morton, G}
}
@article {1051221,
	title = {Immunoincompatibility reactions in corals (Coelenterata)},
	journal = {Adv Exp Med Biol},
	volume = {64},
	year = {1975},
	month = {1975},
	pages = {105-14},
	keywords = {Animals, Cnidaria, Histocompatibility Testing, Phylogeny, Transplantation Immunology, Transplantation, Heterologous, Transplantation, Homologous, Transplantation, Isogeneic},
	issn = {0065-2598},
	author = {Hildemann, W H and Linthicum, D S and Vann, D C}
}
@article {1051241,
	title = {Inhibition of aldehyde reductase by acidic metabolites of the biogenic amines},
	journal = {Biochem Pharmacol},
	volume = {24},
	number = {18},
	year = {1975},
	month = {1975 Sep 15},
	pages = {1731-3},
	keywords = {Aldehyde Oxidoreductases, Animals, Biogenic Amines, Brain, Homovanillic Acid, In Vitro Techniques, Kinetics, NADP, Pyrimidines, Sheep},
	issn = {0006-2952},
	author = {Turner, A J and Hick, P E}
}
@article {1051251,
	title = {Irreversible drug induced parkinsonism (two case reports)},
	journal = {J Assoc Physicians India},
	volume = {23},
	number = {8},
	year = {1975},
	month = {1975 Aug},
	pages = {529-30},
	keywords = {Adult, Humans, Male, Middle Aged, Parkinson Disease, Secondary, Phenothiazines, Prochlorperazine, Trifluoperazine},
	issn = {0004-5772},
	author = {Sahoo, R N and Mitra, G C and Mohanty, P C}
}
@article {1051216,
	title = {Multiple endocrine adenomatosis-I and II},
	journal = {Curr Probl Surg},
	year = {1975},
	month = {1975 Aug},
	pages = {1-51},
	keywords = {Adolescent, Adult, Carcinoma, Child, Child, Preschool, Female, Humans, Male, Middle Aged, Multiple Endocrine Neoplasia, Prognosis, Thyroid Neoplasms, Zollinger-Ellison Syndrome},
	issn = {0011-3840},
	author = {Harrison, T S and Thompson, N W}
}
@article {1051231,
	title = {The purification and characterization of the low molecular weight human folate binding protein using affinity chromatography},
	journal = {Biochemistry},
	volume = {14},
	number = {25},
	year = {1975},
	month = {1975 Dec 16},
	pages = {5422-8},
	abstract = {The low molecular weight folate binding protein (FABP) has been purified 1000-fold to a specific activity of 7.2 gamma g of pteroylglutamic acid (PGA) bound per mg of protein. This purified FABP represents two protein bands that bind PGA on polyacrylamide disc gel electrophoreis, elutes from DEAE-cellulose in 0.001 M phosphate buffer, stains positive with PAS, Elutes from concanavalin A Sepharose affinity columns with methyl alpha-mannoside, and shows three major peaks (pl =6.8, 7.5, 8.2) by isotric focusing. The binding of PGA to purified FABP dependent on pH and is inhibited by urea...},
	keywords = {Carrier Proteins, Chromatography, Affinity, Chromatography, Gel, Clinical Trials as Topic, Electrophoresis, Polyacrylamide Gel, Female, Folic Acid, HeLa Cells, Humans, Hydrogen-Ion Concentration, Milk, Human, Molecular Weight, Urea},
	issn = {0006-2960},
	author = {Waxman, S and Schreiber, C}
}
@article {1051186,
	title = {Characteristics of the dephosphorylated form of phosphorylase purified from rat liver and measurement of its activity in crude liver preparations},
	journal = {Biochim Biophys Acta},
	volume = {410},
	number = {1},
	year = {1975},
	month = {1975 Nov 20},
	pages = {45-60},
	abstract = {The phosphorylated form of liver glycogen phosphorylase (alpha-1,4-glucan : orthophosphate alpha-glucosyl-transferase, EC 2.4.1.1) (phosphorylase a) is active and easily measured while the dephosphorylated form (phosphorylase b), in contrast to the muscle enzyme, has been reported to be essentially inactive even in the presence of AMP. We have purified both forms of phosphorylase from rat liver and studied the characteristics of each. Phosphorylase b activity can be measured with our assay conditions. The phosphorylase b we obtained was stimulated by high concentrations of sulfate, and was a substrate for muscle phosphorylase kinase whereas phosphorylase a was inhibited by sulfate, and was a substrate for liver phosphorylase phosphatase. Substrate binding to phosphorylase b was poor (KM glycogen = 2.5 mM, glucose-1-P = 250 mM) compared to phosphorylase a (KM glycogen = 1.8 mM, KM glucose-1-P = 0.7 mM). Liver phosphorylase b was active in the absence of AMP. However, AMP lowered the KM for glucose-1-P to 80 mM for purified phosphorylase b and to 60 mM for the enzyme in crude extract (Ka = 0.5 mM). Using appropriate substrate, buffer and AMP concentrations, assay conditions have been developed which allow determination of phosphorylase a and 90\% of the phosphorylase b activity in liver extracts. Interconversion of the two forms can be demonstrated in vivo (under acute stimulation) and in vitro with little change in total activity. A decrease in total phosphorylase activity has been observed after prolonged starvation and in diabetes.},
	keywords = {Adenosine Monophosphate, Adrenal Glands, Adrenalectomy, Animals, Buffers, Chickens, Diabetes Mellitus, Fasting, Hydrogen-Ion Concentration, Kinetics, Liver, Muscles, Phosphorylase Kinase, Phosphorylase Phosphatase, Phosphorylases, Rabbits, Rats, Salts},
	issn = {0006-3002},
	author = {Tan, A W and Nuttall, F Q}
}
@article {1051206,
	title = {Conformational and molecular responses to pH variation of the purified membrane adenosine triphosphatase of Micrococcus lysodeikticus},
	journal = {Biochim Biophys Acta},
	volume = {413},
	number = {3},
	year = {1975},
	month = {1975 Dec 16},
	pages = {394-414},
	abstract = {A preparation of ATPase from the membranes of Micrococcus lysodeikticus, solubilized and more than 95\% pure, showed two main bands in analytical polyacrylamide gel electrophoresis. They did not correspond to isoenzymes because one band could be converted into the other by exposure to a mildly alkaline pH value. The conversion was paralleled by changes in molecular weight, circular dichroism and catalytic properties. Denaturation by pH at 25 degrees C was followed by means of circular dichroism, ultracentrifugation and polyacrylamide gel electrophoresis. A large conformational transition took place in the acid range with midpoints at about pH = 3.6 (I = 10(-4) M), 4.3 (I = 0.03 M) and 5.3 (I = 0.1 M). The transition was irreversible. Strong aggregation of the protein occurred in this range of pH. The final product was largely random coil, but even at pH 1.5 dissociation into individual subunits was not complete. However, partial dissociation took place at pH 5 (I = 0.028 M). At this pH value the enzyme was inactive, but 20-30\% of the activity could be recovered when the pH was returned to 7.5. In the alkaline region the midpoint of the transition occurred near pH = 11 (I = 0.028 M). The pK of most of the tyrosine residues of the protein was about 10.9. The unfolding was irreversible and the protein was soon converted into peptide species with molecular weights lower than those determined for the subunits by gel electrophoresis in the presence of sodium dodecyl sulphate. Conventional proteolysis did not account for the transformation.},
	keywords = {Adenosine Triphosphatases, Cell Membrane, Circular Dichroism, Hydrogen-Ion Concentration, Kinetics, Micrococcus, Microscopy, Electron, Molecular Weight, Osmolar Concentration, Protein Conformation, Spectrophotometry, Ultraviolet, Tryptophan, Tyrosine},
	issn = {0006-3002},
	author = {Nieto, M and Mu{\~n}oz, E and Carreira, J and Andreu, J M}
}
@article {1051196,
	title = {Histamine receptors in the vasculature of the rabbit ear},
	journal = {Naunyn Schmiedebergs Arch Pharmacol},
	volume = {291},
	number = {1},
	year = {1975},
	month = {1975},
	pages = {23-9},
	abstract = {Histamine has a dual action on the isolated perfused ear preparation of the rabbit. The amine induced a dose-dependent rise in perfusion pressure when the preparation was perfused with Krebs{\textquoteright} solution. This pressor response was reversed to a depressor effect when meypramine was added to the perfusion fluid. This depressor effect of the amine was also dose-related. Metiamide competitively inhibited the depressor effect of histamine. Prior treatment of the ear vessels with metiamide alone caused an increase in histamine-induced perfusion pressure. From these results it was concluded that the predominant pressor effect of histamine on the vascular bed of the rabbit ear is mediated through the H1-receptors and the depressor effect of the amine through histamine H2-receptors.},
	keywords = {Acetylcholine, Angiotensin II, Animals, Arteries, Ear, Histamine, Histamine H1 Antagonists, In Vitro Techniques, Metiamide, Muscle Contraction, Norepinephrine, Pyrilamine, Rabbits, Receptors, Drug, Vasoconstrictor Agents, Vasodilator Agents, Vasomotor System},
	issn = {0028-1298},
	author = {Ercan, Z S and T{\"u}rker, R K}
}
@article {1051181,
	title = {Inguinal herniography in children},
	journal = {J Am Osteopath Assoc},
	volume = {74},
	number = {12},
	year = {1975},
	month = {1975 Aug},
	pages = {1139-45},
	keywords = {Child, Preschool, Cryptorchidism, Hernia, Inguinal, Humans, Infant, Male, Methods, Radiography},
	issn = {0098-6151},
	author = {Melnick, A and Levyn, M E and Mogul, H N and Berger, R}
}
@article {1051141,
	title = {Characteristics of the noradrenergic innervation of the left atrium in the chick (Gallus gallus domesticus, L.)},
	journal = {Comp Biochem Physiol C},
	volume = {52},
	number = {1},
	year = {1975},
	month = {1975 Oct 01},
	pages = {47-9},
	keywords = {Animals, Atrial Function, Chickens, Cocaine, Heart, Heart Atria, Heart Conduction System, Myocardial Contraction, Phenoxybenzamine, Scopolamine Hydrobromide},
	issn = {0306-4492},
	author = {Bennett, T and Malmfors, T}
}
@article {1051156,
	title = {[Level of nicotinamide coenzymes in the liver and myocardium of rats poisoned with dichlorethane]},
	journal = {Biull Eksp Biol Med},
	volume = {79},
	number = {4},
	year = {1975},
	month = {1975 Apr},
	pages = {58-60},
	abstract = {Experiments were conducted on male rats. A study was made of the content of nicotinamide coenzymes in the liver and myocardium 24 hours after the administration of 0.5 ml of dichloroethane into the stomach. In parallel with disturbance of the morphological structure of the liver and of the myocardium, increase in the activity of alanine and aspargic aminotranspherases in the blood serum, dichloroethane reduced the content of nicotinamide coenzymes and deranged the ratio of their oxidized and reduced forms in these organs.},
	keywords = {Alanine Transaminase, Animals, Aspartate Aminotransferases, Ethylene Dichlorides, Heart, Hydrocarbons, Chlorinated, Liver, Male, Myocardium, NAD, NADP, Rats},
	issn = {0365-9615},
	author = {Natsiuk, M V and Chekman, I S}
}
@article {1051176,
	title = {Radiochemical assay of glutathione S-epoxide transferase and its enhancement by phenobarbital in rat liver in vivo},
	journal = {Biochem Pharmacol},
	volume = {24},
	number = {17},
	year = {1975},
	month = {1975 Sep 01},
	pages = {1569-72},
	keywords = {Animals, Carrier Proteins, Epoxy Compounds, Glutathione, Glutathione Transferase, Hydrogen-Ion Concentration, Liver, Male, Methylcholanthrene, Phenobarbital, Rats, Stimulation, Chemical, Styrenes},
	issn = {0006-2952},
	author = {Marniemi, J and Parkki, M G}
}
@article {1051171,
	title = {[Studies on the action of an anticholinergic agent in combination with a tranquilizer on gastric juice secretion in man]},
	journal = {Arzneimittelforschung},
	volume = {25},
	number = {9},
	year = {1975},
	month = {1975 Sep},
	pages = {1460-3},
	abstract = {A double-blind study with intra-individual comparisons was carried out to investigate the effects of 15 mg of (8r)-3alpha-hydroxy-8-isopropyl-1alphaH-tropanium bromide(+/-)-tropate (Sch 1000), 15 mg Sch 1000 + 10 mg oxazepam, 10 mg oxazepam and placebo with oral administration in randomized sequence on gastric juice volume, amount of acid, concentration and pH values in 12 healthy volunteers. The secretion parameters were measured during a 1-h basal period and a 2-h stimulation period. The gastric juice was obtained in 15 min portions via stomach tube. Stimulation was effected by 1 mug/kg/h pentagastrin via drip infusion. The Friedman test was used for the comparative statistical evaluation, and individual comparisons were carried out by means of the Wilcoxon test (pair-differences rank). The results show that Sch 1000 and Sch 1000 + oxazepam were equal in effect on basal and stimulated secretion volume. As compared with placebo, it was not possible to establish an effect on secretion volume for oxazepam alone. Sch 1000 and Sch 1000 + oxazepam were found to be equipotent in reducing the amount of basal acid, while oxazepam reduced this quantity only during the first 30 min of basal secretion. None of the three active preparations was capable of inhibiting the stimulated acid, although both Sch 1000 preparations produced a clear trend towards lowered mean values. During the basal secretion period, all three test preparations had an inhibiting action on acid concentration, but none of them had a significant effect during the stimulation period. The pH value was savely increased only by Sch 1000 and Sch 1000 + oxazepam, and this even only during the basal period. The results are discussed.},
	keywords = {Adult, Atropine Derivatives, Clinical Trials as Topic, Depression, Chemical, Drug Combinations, Female, Gastric Juice, Humans, Hydrogen-Ion Concentration, Ipratropium, Male, Middle Aged, Oxazepam, Pentagastrin, Time Factors},
	issn = {0004-4172},
	author = {Scherberger, R R and Kaess, H and Br{\"u}ckner, S}
}
@article {1051136,
	title = {A clinical method for the determination of serum gamma-glutamyl transpeptidase},
	journal = {Clin Chim Acta},
	volume = {65},
	number = {1},
	year = {1975},
	month = {1975 Nov 15},
	pages = {21-7},
	abstract = {A simple, highly sensitive and reproducible method for the assay of gamma-glutamyl transpeptidase (EC 2.3.2-) activity is introduced, using gamma-glutamyl-p-nitroanilide as a substrate and glycylglycine as an acceptor in 50 g/l of polyoxyethylene nonylphenol. Serum transpeptidase activity was assayed in 1080 healthy adults, the normal mean value being 14.8 mU/ml. The diagnostic evaluation of the enzyme in various hepatobiliary diseases is also discussed.},
	keywords = {Adult, Biliary Tract Diseases, Detergents, Female, gamma-Glutamyltransferase, Humans, Liver Diseases, Male, Microchemistry, Spectrophotometry},
	issn = {0009-8981},
	author = {Tamaoki, H and Minato, S and Takei, S and Fujisawa, K}
}
@article {1051131,
	title = {Editorial: "Old lamps for new"},
	journal = {Br J Anaesth},
	volume = {47},
	number = {8},
	year = {1975},
	month = {1975 Aug},
	pages = {811-2},
	keywords = {Anesthesia, Inhalation, Arrhythmias, Cardiac, Enflurane, Ethers, Halothane, Humans, Isoflurane, Kidney Diseases, Methoxyflurane, Trichloroethylene, Trifluoroethanol},
	issn = {0007-0912},
	author = {Conway, C M}
}
@article {1051111,
	title = {Hybrid-versus-parental strain reaction. I. Comparative mortality in allogenetic and parental strain male and female mice},
	journal = {J Natl Cancer Inst},
	volume = {55},
	number = {5},
	year = {1975},
	month = {1975 Nov},
	pages = {1213-5},
	abstract = {Lethally irradiated male and female hybrids, parental strains, and the third party strain A mice were inoculated with reciprocal hybrid marrow from donors of the same sex. A graft-versus-host reaction was produced against H-Y antigens of reciprocal hybrids. Although the late mortality in inbred strain males was generally greater than that of females, without further tests this difference was not automatically attributable to an X or a Y chromosome disparity. Hybrids did not recognize the qualitative difference in antigenicity of their reciprocals, but they were able to recognize the quantitatively greater antigenicity of their parental strains, and a hybrid-versus-parental strain reaction occurred. The graft-versus-host reaction in the third party strain A mice was significantly more severe than that produced by hybrid marrow in their reciprocal hybrid recipients, but significantly less severe than that produced in the parental strains. The relationship between antigenicity and responsiveness was such that the severity of the graft-versus-host reactions masked the maternal influences observed with other reciprocal hybrids.},
	keywords = {Animals, Bone Marrow, Bone Marrow Cells, Bone Marrow Transplantation, Female, Graft vs Host Reaction, Histocompatibility Antigens, Hybridization, Genetic, Male, Mice, Mice, Inbred A, Mice, Inbred C3H, Sex Chromosomes, Transplantation, Homologous},
	issn = {0027-8874},
	author = {Uphoff, D E}
}
@article {1051106,
	title = {Increase in acetyl CoA synthetase activity after phenobarbital treatment},
	journal = {Biochem Pharmacol},
	volume = {24},
	number = {18},
	year = {1975},
	month = {1975 Sep 15},
	pages = {1725-7},
	keywords = {Acetate-CoA Ligase, Acetylesterase, Acetylglucosamine, Animals, Coenzyme A Ligases, Cycloheximide, Glucosamine, Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing), Liver, Male, Phenobarbital, Phosphotransferases, Proteins, Rats, Stimulation, Chemical},
	issn = {0006-2952},
	author = {Akamatsu, N and Nakajima, H and Ono, M and Miura, Y}
}
@article {1051116,
	title = {Malathion A and B esterases of mouse liver-I},
	journal = {Biochem Pharmacol},
	volume = {24},
	number = {18},
	year = {1975},
	month = {1975 Sep 15},
	pages = {1713-7},
	keywords = {Animals, Drug Stability, Esterases, Female, Hydrogen-Ion Concentration, Liver, Malathion, Male, Metals, Mice, Sex Factors, Sulfhydryl Compounds},
	issn = {0006-2952},
	author = {Bhagwat, V M and Ramachandran, B V}
}
@article {1051056,
	title = {Action of propranolol on mitochondrial functions--effects on energized ion fluxes in the presence of valinomycin},
	journal = {Biochem Pharmacol},
	volume = {24},
	number = {18},
	year = {1975},
	month = {1975 Sep 15},
	pages = {1701-5},
	keywords = {Adenosine Triphosphatases, Adenosine Triphosphate, Animals, Hydrogen-Ion Concentration, In Vitro Techniques, Mitochondria, Mitochondria, Liver, Mitochondrial Swelling, Nigericin, Oxidative Phosphorylation, Oxygen Consumption, Potassium, Propranolol, Rats, Time Factors, Valinomycin},
	issn = {0006-2952},
	author = {J{\"a}rvisalo, J and Saris, N E}
}
@article {1051076,
	title = {Comparison between procaine and isocarboxazid metabolism in vitro by a liver microsomal amidase-esterase},
	journal = {Biochem Pharmacol},
	volume = {24},
	number = {16},
	year = {1975},
	month = {1975 Aug 15},
	pages = {1517-21},
	keywords = {Amidohydrolases, Animals, Esterases, Hydrogen-Ion Concentration, In Vitro Techniques, Isocarboxazid, Kinetics, Male, Metals, Microsomes, Liver, Phospholipids, Procaine, Proteins, Rats, Subcellular Fractions, Temperature},
	issn = {1873-2968},
	author = {Moroi, K and Sato, T}
}
@article {1051081,
	title = {Dopamine-containing neurons of the substantia nigra and their terminals in the neostriatum},
	journal = {UCLA Forum Med Sci},
	number = {18},
	year = {1975},
	month = {1975},
	pages = {227-64},
	abstract = {Tne ultrastructural and fluorescence histochemical characteristics of the mature rabbit substantia nigra and neostriatum have been reviewed as a frame of reference for the developmental study. Biochemical investigations were reported on neostriatal dopamine concentrations and the relative uptake and accumulation of 3H-dopamine by this tissue from fetal to adult stages, to provide quantitative data for correlation with the fluorexcence information. The development of the neurons of the substantia nigra and their axons which project to the neostriatum has been presented from their appearance at day 14 of gestation to their maturation in early postnatal life. The initial bipolar neuroblasts, which develop in the midline of the caudal mesencephalon, are fluorescent as soon as they emerge from the ependymal zone. Their fluorescent axons, which form the nigroneostriatal pathway, reach the telencephalon at day 16 of gestation and ramify extensively in the putamen by day 20, but do not enter the caudate nucleus until several days later. Some of the early fluorescent axonal profiles in the putamen are extremely large. Electron microscopic study of theis stage suggests that the large fluorescent profiles may correspond to axonal growth cones or early synapses. A distinct substantia nigra, pars compacta and reticulata, can be recognized by fluorescence microscopy by day 20 of gestation. Electron microscopy reveals that the young neurons are multipolar with numerous developing dendrites, some of which exhibit early synaptic junctions. The subsequent maturaition of these cells and the neuropil is described. The fluorescent axons of the substantia nigra grow into the putamen and caudate nucleus in a nonuniform manner forming fluorescent islands throughout the neostriatum in late fetal life. Occasionally, minute beaded fluorescent axons are found. These profiles might correspond to some of the axons with varicosities "en passage" revealed by electron microscopy. In an attempt to identify further the dopamine-containing axon, the ultratructure of adult neostriatum incubated in 5-hydroxydopamine was reported. Axonal varicosities "en passage" containing a dense "tag" in the vesicles were found. Most of the tagged boutons did not exhibit synaptic contacts. The possible significance of these finding s as related to dopamine secretion are discussed.},
	keywords = {Animals, Axons, Biogenic Amines, Caudate Nucleus, Cell Differentiation, Cell Movement, Corpus Striatum, Dopamine, Histocytochemistry, Microscopy, Electron, Microscopy, Fluorescence, Morphogenesis, Neural Pathways, Neurotransmitter Agents, Rabbits, Substantia Nigra, Synapses},
	issn = {0082-7134},
	author = {Tennyson, V M and Mytilineou, C and Heikkila, R and Barrett, R E and Cohen, G and C{\^o}t{\'e}, L and Duffy, P E and Marco, L}
}
@article {1051086,
	title = {Poly(8-aminoguanylic acid): formation of ordered self-structures and interaction with poly(cytidylic acid)},
	journal = {Biochemistry},
	volume = {14},
	number = {23},
	year = {1975},
	month = {1975 Nov 18},
	pages = {5033-45},
	abstract = {Poly(8-aminoguanylic acid) has in neutral solution a novel ordered structure of high stability. The 8-amino group permits formation of three hydrogen bonds between two residues along the "top", or long axis, of the purines. The usual hydrogen bonding protons and Watson-Crick pairing sites are not involved in the association. The bonding scheme has a twofold rotation axis and is hemiprotonated at N(7). Poly(8NH2G) is converted by alkaline titration (pK = 9.7) to a quite different ordered structure, which is the favored form over the range approximately pH 10-11. The bonding scheme appears to be composed of a planar, tetrameric array of guanine residues, in which the 8-amino group does not participate in interbase hydrogen bonding. Poly (8NH2G) does not interact with poly(C) in neutral solution because of the high stability of the hemiprotonated G-G self-structure. Titration to the alkaline plateau, however, permits ready formation of a two-stranded Watson-Crick helix. In contrast to the monomer 8NH2GMP, poly(8NH2G) does not form a triple helix with poly(C) under any conditions. The properties of the ordered structures are interpreted in terms of a strong tendency of the 8-amino group to form a third interbase hydrogen bond, when this possibility is not prevented by high pH.},
	keywords = {Binding Sites, Circular Dichroism, Drug Stability, Escherichia coli, Hydrogen Bonding, Hydrogen-Ion Concentration, Micrococcus, Models, Molecular, Nucleic Acid Conformation, Poly C, Poly G, Polyribonucleotide Nucleotidyltransferase, Polyribonucleotides, Spectrophotometry, Infrared, Spectrophotometry, Ultraviolet, Temperature},
	issn = {0006-2960},
	author = {Hattori, M and Frazier, J and Miles, H T}
}
@article {1051071,
	title = {Studies of oxygen binding energy to hemoglobin molecule},
	journal = {Biochem Biophys Res Commun},
	volume = {66},
	number = {4},
	year = {1975},
	month = {1975 Oct 27},
	pages = {1424-31},
	keywords = {Binding Sites, Cobalt, Hemoglobins, Humans, Hydrogen-Ion Concentration, Iron, Ligands, Mathematics, Oxygen, Oxyhemoglobins, Protein Binding, Spectrum Analysis},
	issn = {0006-291X},
	author = {Chow, Y W and Pietranico, R and Mukerji, A}
}
@article {1051096,
	title = {Subtilopeptidase A isoenzyme system. Interaction with serum components and its importance for quantitative immunoelectrophoresis},
	journal = {Biochem J},
	volume = {151},
	number = {1},
	year = {1975},
	month = {1975 Oct},
	pages = {149-55},
	abstract = {A method was developed which involved electroimmunoassay and crossed immunoelectrophoresis of subtilopeptidase A (EC 3.4.21.14). Initial trials with unfractionated antiserum were not successful and interaction of the enzyme with non-immunoglobulin serum components were shown to be the cause of the failures. Quantitative immunoelectrophoresis was possible when purified immunoglobulins were used. A pH of 6.5 (lower than the usual pH 8.6) was necessary to obtain a proper baseline definition. Subtilopeptidase A was confirmed as a multiple isoenzyme system. Qualitative inter-batch variations were detected. Di-isopropyl phosphorofluoridate inhibition altered the electrophoretic pattern, but no loss of antigenic determinants was observed.},
	keywords = {Animals, Humans, Hydrogen-Ion Concentration, Immunoassay, Immunoelectrophoresis, Two-Dimensional, Immunoglobulins, Isoenzymes, Isoflurophate, Rabbits, Subtilisins},
	issn = {0264-6021},
	author = {Verbruggen, R}
}
@article {1051026,
	title = {Metal substitutions incarbonic anhydrase: a halide ion probe study},
	journal = {Biochem Biophys Res Commun},
	volume = {66},
	number = {4},
	year = {1975},
	month = {1975 Oct 27},
	pages = {1281-6},
	keywords = {Animals, Binding Sites, Cadmium, Carbonic Anhydrases, Cattle, Humans, Hydrogen-Ion Concentration, Magnetic Resonance Spectroscopy, Mercury, Protein Binding, Protein Conformation, Zinc},
	issn = {0006-291X},
	author = {Smith, R J and Bryant, R G}
}
@article {1051036,
	title = {The myofilament lattice: studies on isolated fibers. IV. Lattice equilibria in striated muscle},
	journal = {J Mechanochem Cell Motil},
	volume = {3},
	number = {2},
	year = {1975},
	month = {1975},
	pages = {111-21},
	abstract = {Accounts of similarities between the thick filament lattice of striated muscle and smectic liquid-crystalline structures have focused upon an equilibrium between electrostatic (repulsive) and van der Waal{\textquoteright}s (attractive) forces. In living, intact muscle the fiber volume constitutes an additional important parameter which influences the amount of interaxial separation between the filaments. This is demonstrable by comparison of the lattice behavior of living fibers with that of fibers from which the sarcolemma has either been removed or made leaky by glycerination. These comparisons were made mainly by low-angle X-ray diffraction under conditions of changes in sarcomere length, ionic strength or osmolarity, and pH. Single fibers with the sarcolemma removed and glycerinated muscle have lattices which behave in accord with equilibrium liquid-crystalline systems in which the thick filament spacing is determined by the balance between electrostatic and van der Waal{\textquoteright}s forces. Conversely, osmotic and shortening studies demonstrate that the living, intact muscle has a lattice which behaves in accord with the so-called non-equilibrium (volume-constrained) liquid-crystalline condition in which the interaxial separation between the thick filaments is solely due to the amount of volume available as determined by the Donnan steady-state across the sarcolemma.},
	keywords = {Animals, Astacoidea, Binding Sites, Hydrogen-Ion Concentration, Mathematics, Muscles, Myosins, Osmotic Pressure, Protein Binding, Protein Conformation},
	issn = {0091-6552},
	author = {April, E W}
}
@article {1051031,
	title = {Phobias complicating treatment of uterine carcinoma},
	journal = {Br Med J},
	volume = {4},
	number = {5994},
	year = {1975},
	month = {1975 Nov 22},
	pages = {440},
	keywords = {Adenocarcinoma, Animals, Behavior Therapy, Desensitization, Psychologic, Female, Humans, Middle Aged, Phobic Disorders, Uterine Neoplasms},
	issn = {0007-1447},
	author = {Lloyd, G and Deakin, H G}
}
@article {1051041,
	title = {The reaction between the superoxide anion radical and cytochrome c},
	journal = {Biochim Biophys Acta},
	volume = {408},
	number = {3},
	year = {1975},
	month = {1975 Dec 11},
	pages = {215-22},
	abstract = {1. The superoxide anion radical (O2-) reacts with ferricytochrome c to form ferrocytochrome c. No intermediate complexes are observable. No reaction could be detected between O2- and ferrocytochrome c. 2. At 20 degrees C the rate constant for the reaction at pH 4.7 to 6.7 is 1.4-10(6) M-1. S -1 and as the pH increases above 6.7 the rate constant steadily decreases. The dependence on pH is the same for tuna heart and horse heart cytochrome c. No reaction could be demonstrated between O2- and the form of cytochrome c which exists above pH approximately 9.2. The dependence of the rate constant on pH can be explained if cytochrome c has pKs of 7.45 and 9.2, and O2- reacts with the form present below pH 7.45 with k = 1.4-10(6) M-1 - S-1, the form above pH 7.45 with k = 3.0- 10(5) M-1 - S-1, and the form present above pH 9.2 with k = 0. 3. The reaction has an activation energy of 20 kJ mol-1 and an enthalpy of activation at 25 degrees C of 18 kJ mol-1 both above and below pH 7.45. It is suggested that O2- may reduce cytochrome c through a track composed of aromatic amino acids, and that little protein rearrangement is required for the formation of the activated complex. 4. No reduction of ferricytochrome c by HO2 radicals could be demonstrated at pH 1.2-6.2 but at pH 5.3, HO2 radicals oxidize ferrocytochrome c with a rate constant of about 5-10(5)-5-10(6) M-1 - S-1.},
	keywords = {Animals, Binding Sites, Calorimetry, Cytochrome c Group, Free Radicals, Horses, Hydrogen-Ion Concentration, Kinetics, Myocardium, Oxygen, Protein Binding, Spectrophotometry, Spectrophotometry, Ultraviolet, Superoxides, Temperature, Thermodynamics},
	issn = {0006-3002},
	author = {Butler, J and Jayson, G G and Swallow, A J}
}
@article {1051046,
	title = {Seasonal variations in the composition of urine in relation to calcium stone-formation},
	journal = {Clin Sci Mol Med},
	volume = {49},
	number = {6},
	year = {1975},
	month = {1975 Dec},
	pages = {597-602},
	abstract = {1. A retrospective cross-sectional study was carried out on data derived from single 24 h urine collections from 246 male idiopathic calcium stone-formers. 2. The daily urine volume and pH and the exretions of calcium, oxalate, phosphate, creatinine and magnesium were related to the time of year when the urine was collected, and the saturation of urine with calcium oxalate and octocalcium phosphate calculated for each month. 3. There were significant seasonal variations in the urinary excretion of calcium and oxalate, each showing a maximum during the summer months and a minimum in the winter. There was no significant seasonal variation in urinary pH, volume, creatinine, phosphate or magnesium. 4. There was a significant increase in the saturation of urine with calcium oxalate and a trend towards higher saturation levels of octo-calcium phosphate in the summer. These changes were dependent only on the seasonal variation in urinary calcium and oxalate and not on urine volume. 5. A retrospective study of the seasonal incidence of stone episodes among these 246 stone-formers showed that the rate of stone passage per month was 50\% higher in the summer than in the winter. There was no significant seasonal variation in the incidence of stones removed surgically.},
	keywords = {Calcium, Creatinine, England, Humans, Hydrogen-Ion Concentration, Magnesium, Male, Oxalates, Phosphates, Retrospective Studies, Seasons, Urinary Calculi, Urine},
	issn = {0301-0538},
	author = {Robertson, W G and Peacock, M and Marshall, R W and Speed, R and Nordin, B E}
}
@article {1050976,
	title = {A comparison of the substrate specificities of endo-beta-N-acetylglucosaminidases from Streptomyces griseus and Diplococcus Pneumoniae},
	journal = {Biochem Biophys Res Commun},
	volume = {67},
	number = {1},
	year = {1975},
	month = {1975 Nov 03},
	pages = {455-62},
	keywords = {Acetylglucosaminidase, Fucose, Hexosaminidases, Kinetics, Oligosaccharides, Species Specificity, Streptococcus pneumoniae, Streptomyces griseus, Structure-Activity Relationship},
	issn = {0006-291X},
	author = {Tarentino, A L and Maley, F}
}
@article {1051001,
	title = {The effect of adrenaline and of alpha- and beta-adrenergic blocking agents on ATP concentration and on incorporation of 32Pi into ATP in rat fat cells},
	journal = {Biochem Pharmacol},
	volume = {24},
	number = {18},
	year = {1975},
	month = {1975 Sep 15},
	pages = {1659-62},
	keywords = {Adenosine Triphosphate, Adipose Tissue, Adrenergic alpha-Antagonists, Adrenergic beta-Antagonists, Animals, Epinephrine, Hexokinase, In Vitro Techniques, Luciferases, Male, Oxygen Consumption, Phenoxybenzamine, Phosphorus, Phosphorus Radioisotopes, Propranolol, Rats, Time Factors},
	issn = {0006-2952},
	author = {Stein, J M}
}
@article {1050991,
	title = {Effect of chloroquine on cultured fibroblasts: release of lysosomal hydrolases and inhibition of their uptake},
	journal = {Biochem Biophys Res Commun},
	volume = {66},
	number = {4},
	year = {1975},
	month = {1975 Oct 27},
	pages = {1338-43},
	keywords = {Biological Transport, Cells, Cultured, Cerebroside-Sulfatase, Chloroquine, Dextrans, Fibroblasts, Glucuronidase, Humans, Leukodystrophy, Metachromatic, Lysosomes, Pinocytosis, Skin, Sulfatases},
	issn = {1090-2104},
	author = {Wiesmann, U N and DiDonato, S and Herschkowitz, N N}
}
@article {1050996,
	title = {Lysosomal hydrolases of the epidermis. 2. Ester hydrolases},
	journal = {Br J Dermatol},
	volume = {93},
	number = {4},
	year = {1975},
	month = {1975 Oct},
	pages = {391-8},
	abstract = {Five distinct ester hydrolases (EC 3-1) have been characterized in guinea-pig epidermis. These are carboxylic esterase, acid phosphatase, pyrophosphatase, and arylsulphatase A and B. Their properties are consistent with those of lysosomal enzymes.},
	keywords = {Acid Phosphatase, Animals, Carboxylic Ester Hydrolases, Cerebroside-Sulfatase, Chondro-4-Sulfatase, Guinea Pigs, Hydrogen-Ion Concentration, Hydrolases, Kinetics, Lysosomes, Pyrophosphatases, Skin},
	issn = {0007-0963},
	author = {Mier, P D and van den Hurk, J J}
}
@article {1050956,
	title = {Atomic models for the polypeptide backbones of myohemerythrin and hemerythrin},
	journal = {Biochem Biophys Res Commun},
	volume = {66},
	number = {4},
	year = {1975},
	month = {1975 Oct 27},
	pages = {1349-56},
	keywords = {Animals, Cnidaria, Computers, Hemerythrin, Metalloproteins, Models, Molecular, Muscle Proteins, Protein Conformation, Species Specificity},
	issn = {1090-2104},
	author = {Hendrickson, W A and Ward, K B}
}
@article {1050971,
	title = {Digitoxin metabolism by rat liver microsomes},
	journal = {Biochem Pharmacol},
	volume = {24},
	number = {17},
	year = {1975},
	month = {1975 Sep 01},
	pages = {1639-41},
	keywords = {Animals, Chromatography, Thin Layer, Digitoxigenin, Digitoxin, Hydroxylation, In Vitro Techniques, Male, Microsomes, Liver, NADP, Rats, Time Factors},
	issn = {1873-2968},
	author = {Schmoldt, A and Benthe, H F and Haberland, G}
}
@article {1050941,
	title = {Effect of sodium nitrate loading on electrolyte transport by the renal tubule},
	journal = {Am J Physiol},
	volume = {229},
	number = {3},
	year = {1975},
	month = {1975 Sep},
	pages = {746-53},
	abstract = {Effects of sodium nitrate were compared with sodium chloride loading on transport of electrolytes by the nephron. Maximal levels of free water clearance/clomerular filtration rate (CH2O/GFR) averaged 8.4\% with nitrate loading and 14.4\% with saline loading. Since ethacrynic acid and chlorothiazide exert their major natriuretic effect in the distal nephron, the increment in Na ad Cl reabsorbed beyond the proximal tubule. The administration of these agents resulted in an increase in fractional sodium excretion (CNa/GFR) of 21.1\%, urinary sodium excretion (UNaV) of 1,126 mueq/min, and urinary chloride excretion (UClV) of 848 mueq/min during nitrate loading compared with an increase in CNa/GFR of 37.6\%, UNaV of 2,362 mueq/min, and UClV of 2,397 mueq/min during saline loading. The smaller diuretic-induced increment in Na and Cl excretion in the nitrate studies suggests, as do the hydrated studies, that less Cl and Na are reabsorbed in the distal nephron during nitrate than saline loading. At every level of UNaV, fractional bicarbonate reabsorption was higher, urine pH was lower, and urinary potassium excretion (UKV) was higher in the nitrate studies. Thus, compared with saline loading, sodium nitrate decreases chloride and sodium reabsorption in the distal nephron. The higher hydrogen and potassium secretion in the nitrate studies may be consequent to the decreased ability of the distal nephron to reabsorb chloride.},
	keywords = {Animals, Bicarbonates, Biological Transport, Chlorides, Chlorothiazide, Diuresis, Dogs, Electrolytes, Ethacrynic Acid, Glomerular Filtration Rate, Hydrogen-Ion Concentration, Kidney Tubules, Nitrates, Potassium, Sodium, Sodium Chloride, Urine},
	issn = {0002-9513},
	author = {Kahn, T and Bosch, J and Levitt, M F and Goldstein, M H}
}
@article {1050946,
	title = {Effects of 5,6-dihydroxytryptamine on tyrosine-hydroxylase activity in central catecholaminergic neurons of the rat},
	journal = {Biochem Pharmacol},
	volume = {24},
	number = {18},
	year = {1975},
	month = {1975 Sep 15},
	pages = {1739-42},
	keywords = {5,6-Dihydroxytryptamine, Animals, Brain, Catecholamines, Cerebral Cortex, Cisterna Magna, Corpus Striatum, In Vitro Techniques, Injections, Male, Neurons, Rats, Rats, Inbred Strains, Stimulation, Chemical, Substantia Nigra, Time Factors, Tryptamines, Tyrosine 3-Monooxygenase},
	issn = {0006-2952},
	author = {Renaud, B and Buda, M and Lewis, B D and Pujol, J F}
}
@article {1050936,
	title = {Letter: Duration of action of AH8165},
	journal = {Br J Anaesth},
	volume = {47},
	number = {9},
	year = {1975},
	month = {1975 Sep},
	pages = {1033},
	keywords = {Dose-Response Relationship, Drug, Hemodynamics, Humans, Pyridinium Compounds, Time Factors},
	issn = {0007-0912},
	author = {Thornton, J A and Harrison, M J}
}
@article {1050931,
	title = {Maturation of the adrenal medulla--IV. Effects of morphine},
	journal = {Biochem Pharmacol},
	volume = {24},
	number = {16},
	year = {1975},
	month = {1975 Aug 15},
	pages = {1469-74},
	keywords = {Adrenal Medulla, Aging, Animals, Animals, Newborn, Body Weight, Catecholamines, Dopamine beta-Hydroxylase, Epinephrine, Female, Humans, In Vitro Techniques, Maternal-Fetal Exchange, Metaraminol, Morphine, Morphine Dependence, Pregnancy, Rats, Tyrosine 3-Monooxygenase},
	issn = {1873-2968},
	author = {Randerson, James, T and Slotkin, T A}
}
@article {1050951,
	title = {The origin of the alkaline inactivation of pepsinogen},
	journal = {Biochemistry},
	volume = {14},
	number = {24},
	year = {1975},
	month = {1975 Dec 02},
	pages = {5253-6},
	abstract = {Above pH 8.5, pepsinogen is converted into a form which cannot be activated to pepsin on exposure to low pH. Intermediate exposure to neutral pH, however, returns the protein to a form which can be activated. Evidence is presented for a reversible, small conformational change in the molecule, distinct from the unfolding of the protein. At the same time, the molecule is converted to a form of limited solubility, which is precipitated at low pH, where activation is normally seen. The results are interpreted in terms of the peculiar structure of the pepsinogen molecule. Titration of the basic NH2-terminal region produced an open form, which can return to the native form at neutral pH, but which is maintained at low pH by neutralization of carboxylate groups in the pepsin portion.},
	keywords = {Hemoglobins, Hydrogen-Ion Concentration, Kinetics, Pepsin A, Pepsinogens, Protein Conformation, Spectrophotometry, Ultraviolet},
	issn = {0006-2960},
	author = {McPhie, P}
}
@article {1050966,
	title = {Preparation and characterization of an enzymatically active immobilized derivative of myosin},
	journal = {Biochim Biophys Acta},
	volume = {410},
	number = {1},
	year = {1975},
	month = {1975 Nov 20},
	pages = {178-92},
	abstract = {Purified skeletal muscle myosin (EC 3.6.1.3) has been covalently bound to Sepharose 4B by the cyanogen bromide procedure. The resulting complex, Sepharose-Myosin, possesses adenosine triphosphatase activity and is relatively stable for long periods of time. Under optimal binding conditions, approximately 33\% of the specific ATPase activity of the bound myosin is retained. Polyacrylamide gel electrophoresis of polypeptides released from denatured Sepharose-Myosin indicates that 85\% of the myosin is attached to the agarose beads through the heavy chains and the remainder through the light chains, in agreement with predictions of binding and release based upon either the lysine contents or molecular weights of themyosin subunits. The adenosine triphosphatase of the immobilized myosin has been investigated under conditions of varying pH, ionic strength, and cation concentration. The ATPase profiles of immobilized myosin are quite similar to those for free myosin, however subtle differences are found. The Sepharose-Myosin ATPase is not as sensitive as myosin to alterations in salt concentration and the apparent KM is approximately two-fold higher than that of myosin. These differences are probably due to chemical modification in the region of the attachment site(s) to the agarose beads and hydration and diffusion limitations imposed by the polymeric agarose matrix.},
	keywords = {Actins, Adenosine Triphosphatases, Animals, Calcium, Chickens, Chromatography, Affinity, Edetic Acid, Enzyme Activation, Female, Hydrogen-Ion Concentration, Molecular Weight, Muscles, Myosins, Osmolar Concentration, Potassium Chloride, Protein Binding, Sepharose},
	issn = {0006-3002},
	author = {Elgart, E S and Gusovsky, T and Rosenberg, M.D.}
}
@article {1050961,
	title = {Reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent formation and breakdown of hydrogen peroxide during mixed function oxidation reactions in liver microsomes},
	journal = {Arch Biochem Biophys},
	volume = {171},
	number = {2},
	year = {1975},
	month = {1975 Dec},
	pages = {385-97},
	keywords = {Animals, Azides, Ethanol, Horseradish Peroxidase, Hydrogen Peroxide, Kinetics, Male, Methylcholanthrene, Microsomes, Liver, Mixed Function Oxygenases, NADP, Oxidoreductases, Phenobarbital, Pregnenolone, Rats, Scopoletin},
	issn = {0003-9861},
	author = {Hildebraunt, A G and Roots, I}
}
@article {702881,
	title = {Delineation of the intimate details of the backbone conformation of pyridine nucleotide coenzymes in aqueous solution},
	journal = {Biochem Biophys Res Commun},
	volume = {66},
	number = {4},
	year = {1975},
	month = {1975 Oct 27},
	pages = {1173-9},
	keywords = {Fourier Analysis, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Conformation, NAD, NADP, Structure-Activity Relationship, Temperature},
	issn = {1090-2104},
	author = {Bose, K S and Sarma, R H}
}
@article {702876,
	title = {Influence of a new virostatic compound on the induction of enzymes in rat liver},
	journal = {Arzneimittelforschung},
	volume = {25},
	number = {9},
	year = {1975},
	month = {1975 Sep},
	pages = {1426-9},
	abstract = {The virostatic compound N,N-diethyl-4-[2-(2-oxo-3-tetradecyl-1-imidazolidinyl)-ethyl]-1-piperazinecarboxamide-hydrochloride (5531) was analyzed as to its effect on the induction of tryptophan-pyrrolase and tyrosineaminotransferase in rat liver. 1. The basic activity of the enzymes was not influenced by the substance either in normal or in adrenalectomized animals. 2. The induction of the enzymes by cortisone increased in the presence of the compound whereas the substrate induction remained unchanged. 3. The induction of tyrosine-aminotransferase by dexamethasonephosphate in tissue culture is inhibited if the dose of compound 5531 is higher than 5 mug/ml.},
	keywords = {Adrenalectomy, Animals, Antiviral Agents, Cortisone, Culture Techniques, Dose-Response Relationship, Drug, Enzyme Induction, Female, Imidazoles, Liver, Piperazines, Rats, Time Factors, Tryptophan Oxygenase, Tyrosine, Tyrosine Transaminase},
	issn = {0004-4172},
	author = {Kr{\"o}ger, H and Donner, I and Skiello, G}
}
@article {702841,
	title = {Anaerobic glycolysis in normal human erythrocytes incubated in vitro with sodium salicylate.},
	journal = {Clin Sci Mol Med},
	volume = {49},
	number = {5},
	year = {1975},
	month = {1975 Nov},
	pages = {375-84},
	abstract = {1. Some effects of sodium salicylate upon anaerobic glycolysis have been studied in normal human erythrocytes incubated for up to 6 h at 37 degrees C in autologous sera. 2. Both glucose consumption and lactate production were stimulated by concentrations of salicylate up to 60 mmol/l but at the highest concentration used (90 mmol/l) an initial stimulus was followed by inhibition of glycolysis. 3. Losses occurred of adenosine 5{\textquoteright}-triphosphate (ATP), adenosine 5{\textquoteright}-diphosphate (ADP) and adenosine 5{\textquoteright}-phosphate(AMP)at higher concentrations of salicylate and there was a concomitant increase of inorganic phosphate. 4. Other phosphate esters underwent concentration changes at higher concentrations of salicylate that reflected inadequate concentrations of ATP for glycolysis. 5. The rates of sodium efflux from, and potassium influx into, erythrocytes were unaffected by the presence of salicylate at concentrations sufficient to stimulate glycolysis.},
	keywords = {Adenosine Diphosphate, Adenosine Monophosphate, Adenosine Triphosphate, Blood Glucose, Dose-Response Relationship, Drug, Erythrocytes, Glycolysis, Hematocrit, Humans, Hydrogen-Ion Concentration, In Vitro Techniques, Lactates, Phosphates, Potassium, Pyruvates, Sodium, Sodium Salicylate},
	issn = {0301-0538},
	author = {Worathumrong, N and Grimes, A J}
}
@article {702831,
	title = {Arginine decarboxylase from Lathyrus sativus seedlings. Purification and properites.},
	journal = {Eur J Biochem},
	volume = {59},
	number = {2},
	year = {1975},
	month = {1975 Nov 15},
	pages = {377-86},
	abstract = {Arginine decarboxylase which makes its appearance in Lathyrus sativus seedlings after 24 h of seed germination reaches its highest level around 5-7 days, the cotyledons containing about 60\% of the total activity in the seedlings at day 5. The cytosol enzyme was purified 977-fold from whole seedlings by steps involving manganese chloride treatment, ammonium sulphate and acetone fractionations, positive adsorption on alumina C-gamma gel, DEAE-Sephadex chromatography followed by preparative disc gel electrophoresis. The enzyme was shown to be homogeneous by electrophoretic and immunological criteria, had a molecular weight of 220,000 and appears to be a hexamer with identical subunits. The optimal pH and temperature for the enzyme activity were 8.5 and 45 degrees C respectively. The enzyme follows typical Michaelis-Menten kinetics with a Km value of 1.73 mM for arginine. Though Mn2+ at lower concentrations stimulated the enzyme activity, there was no dependence of the enzyme on any metal for the activity. The arginine decarboxylase of L. sativus is a sulfhydryl enzyme. The data on co-factor requirement, inhibition by carbonyl reagents, reducing agents and pyridoxal phosphate inhibitors, and a partial reversal by pyridoxal phosphate of inhibition by pyridoxal-HCl suggests that pyridoxal 5{\textquoteright}-phosphate is involved as a co-factor for the enzyme. The enzyme activity was inhibited competitively by various amines including the product agmatine. Highest inhibition was obtained with spermine and arcain. The substrate analogue, L-canavanine, homologue L-homoarginine and other basic amino acids like L-lysine and L-ornithine inhibited the enzyme activity competitively, homoarginine being the most effective in this respect.},
	keywords = {Amino Acids, Carboxy-Lyases, Cytosol, Drug Stability, Hydrogen-Ion Concentration, Immunodiffusion, Kinetics, Macromolecular Substances, Manganese, Molecular Weight, Plant Development, Plants, Pyridoxal Phosphate, Subcellular Fractions, Sulfhydryl Reagents, Temperature},
	issn = {0014-2956},
	author = {Ramakrishna, S and Adiga, P R}
}
@article {702826,
	title = {Formate assay in body fluids: application in methanol poisoning},
	journal = {Biochem Med},
	volume = {13},
	number = {2},
	year = {1975},
	month = {1975 Jun},
	pages = {117-26},
	keywords = {Aldehyde Oxidoreductases, Animals, Body Fluids, Carbon Dioxide, Formates, Haplorhini, Humans, Hydrogen-Ion Concentration, Kinetics, Methanol, Methods, Pseudomonas},
	issn = {0006-2944},
	author = {Makar, A B and McMartin, K E and Palese, M and Tephly, T R}
}
@article {702846,
	title = {[The organization of health education meetings, verbal reports, carnivals, reader{\textquoteright}s conferences].},
	journal = {Feldsher Akush},
	volume = {40},
	number = {9},
	year = {1975},
	month = {1975 Sep},
	pages = {31-4},
	keywords = {Congresses as Topic, Exhibits as Topic, Health Education, Methods, USSR},
	issn = {0014-9772},
	author = {Shibaeva, A N}
}
@article {702836,
	title = {Plasma binding and disposition of local anesthetics.},
	journal = {Int Anesthesiol Clin},
	volume = {13},
	number = {4},
	year = {1975},
	month = {1975 Winter},
	pages = {33-59},
	keywords = {Anesthetics, Local, Animals, Blood, Female, Fetal Blood, Humans, Hydrogen-Ion Concentration, Pregnancy, Protein Binding},
	issn = {0020-5907},
	author = {Tucker, G T}
}
@article {702871,
	title = {Possible involvement of GABA in the central actions of benzodiazepines.},
	journal = {Psychopharmacol Bull},
	volume = {11},
	number = {4},
	year = {1975},
	month = {1975 Oct},
	pages = {58-9},
	keywords = {Aminobutyrates, Aminooxyacetic Acid, Animals, Anti-Anxiety Agents, Benzodiazepines, Cats, gamma-Aminobutyric Acid, In Vitro Techniques, Mice, Neurons},
	issn = {0048-5764},
	author = {Haefely, W and Kulcs{\'a}r, A and M{\"o}hler, H}
}
@article {702851,
	title = {Purification and some enzymatic properties of the chitosanase from Bacillus R-4 which lyses Rhizopus cell walls.},
	journal = {Biochim Biophys Acta},
	volume = {410},
	number = {1},
	year = {1975},
	month = {1975 Nov 20},
	pages = {145-55},
	abstract = {A strain of Bacillus sp (Bacillus R-4) produces a protease and a carbohydrolase both of which have the ability to lyse Rhizopus cell walls. Of the enzymes, the carbohydrolase has been purified to an ultracentrifugally and electrophoretically homogeneous state, and identified as a chitosanase. The enzyme was active on glycol chitosan as well as chitosan. Molecular weight of the purified enzyme was estimated as 31 000 and isoelectric point as pH 8.30. The enzyme was most active at pH 5.6 and at 40 degrees C with either Rhizopus cell wall or glycol chitosan as substrate, and was stable over a range of pH 4.5 to 7.5 at 40 degrees C for 3 h. The activity was lost by sulfhydryl reagents and restored by either reduced glutathione of L-cysteine. An abrupt decrease in viscosity of the reaction mixture suggested an endowise cleavage of chitosan by this enzyme.},
	keywords = {Bacillus, Cations, Divalent, Cell Wall, Citrates, Drug Stability, Edetic Acid, Glycoside Hydrolases, Hydrogen-Ion Concentration, Kinetics, Molecular Weight, Polysaccharides, Rhizopus, Sulfhydryl Reagents, Temperature},
	issn = {0006-3002},
	author = {Tominaga, Y and Tsujisaka, Y}
}
@article {1051126,
	title = {[Fused vertebrae in archeological skeletal material]},
	journal = {Anthropol Anz},
	volume = {33},
	number = {3},
	year = {1972},
	month = {1972 Jun},
	pages = {258-66},
	keywords = {Cervical Vertebrae, Czechoslovakia, Female, History, Ancient, History, Medieval, Humans, Lumbar Vertebrae, Male, Middle Aged, Paleopathology, Polymyalgia Rheumatica, Spinal Diseases, Spondylitis, Spondylitis, Ankylosing, Thoracic Vertebrae, Tuberculosis, Spinal},
	issn = {0003-5548},
	author = {Vyhn{\'a}nek, L}
}
@article {1051151,
	title = {[Arkadii Nikolaevich Tsellarius]},
	journal = {Klin Khir},
	volume = {6},
	year = {1970},
	month = {1970 Jun},
	pages = {89},
	keywords = {General Surgery, History, 20th Century, Occupational Medicine, Railroads, USSR}
}
@article {1051066,
	title = {Isolation of chloroplast envelope membranes},
	journal = {Nature},
	volume = {228},
	number = {5278},
	year = {1970},
	month = {1970 Dec 26},
	pages = {1347-9},
	keywords = {Chlorophyll, Chloroplasts, Membranes, Microscopy, Electron, Microscopy, Phase-Contrast, Plant Proteins, Plants, Edible},
	issn = {0028-0836},
	author = {Mackender, R O and Leech, R M}
}
@article {1051376,
	title = {[Research on chlorophos-32 elimination from rabbit and ewe organisms]},
	journal = {Bull Acad Vet Fr},
	volume = {42},
	number = {9},
	year = {1969},
	month = {1969 Nov},
	pages = {889-95},
	keywords = {Animals, Feces, Insecticides, Intestinal Absorption, Male, Milk, Phosphorus Isotopes, Rabbits, Sheep, Time Factors},
	issn = {0001-4192},
	author = {Petritchev, M and Lazarov, V}
}
@article {1051351,
	title = {Instrumental conditioning of thalamogenic movements and its dependence on the cerebral cortex},
	journal = {Acta Biol Exp (Warsz)},
	volume = {29},
	number = {1},
	year = {1969},
	month = {1969},
	pages = {17-28},
	keywords = {Animals, Cats, Cerebral Cortex, Conditioning, Operant, Motor Activity, Thalamus},
	issn = {0365-0820},
	author = {Tarnecki, R and Konorski, J}
}
@article {1051301,
	title = {Conformational properties of poly-L-ornithine in aqueous solution},
	journal = {Ric Sci},
	volume = {39},
	number = {1},
	year = {1969},
	month = {1969 Jan},
	pages = {61-7},
	keywords = {Chemical Phenomena, Chemistry, Physical, Ornithine, Solutions, Water},
	issn = {0035-5011},
	author = {Conio, G and Patrone, E and Tealdi, A and Bianchi, E}
}
@article {1050986,
	title = {Articular cartilage changes in early arthritis},
	journal = {Bull Hosp Joint Dis},
	volume = {30},
	number = {2},
	year = {1969},
	month = {1969 Oct},
	pages = {136-52},
	keywords = {Adult, Arthritis, Reactive, Arthritis, Rheumatoid, Biopsy, Cartilage, Articular, Diabetes Mellitus, Female, Fluorescent Antibody Technique, Gangrene, Humans, Hyaluronoglucosaminidase, Knee Joint, Male, Middle Aged, Osteoarthritis, Peptide Hydrolases, Polysaccharides, Synovial Fluid, Synovial Membrane},
	author = {Janis, R and Hamerman, D}
}
@article {1051021,
	title = {[Professor Dr. med. Heinrich Meng. On his 80th birthday]},
	journal = {Prax Kinderpsychol Kinderpsychiatr},
	volume = {17},
	number = {2},
	year = {1968},
	month = {1968 Feb-Mar},
	pages = {33-4},
	keywords = {History of Medicine, Psychiatry, Switzerland},
	issn = {0032-7034},
	author = {Battegay, R}
}
@article {1051406,
	title = {Uptake of "single-stranded" DNA in Hemophilus influenzae and its ability to transform},
	journal = {J Mol Biol},
	volume = {16},
	number = {2},
	year = {1966},
	month = {1966 Apr},
	pages = {317-27},
	keywords = {DNA, Bacterial, Haemophilus influenzae, Hydrogen-Ion Concentration, Kinetics, Protoplasts, Ultracentrifugation},
	issn = {0022-2836},
	author = {Postel, E H and Goodgal, S H}
}
@article {1051166,
	title = {[Circulatory homeostasis in physical exertion]},
	journal = {Stud Cercet Fiziol},
	volume = {11},
	number = {2},
	year = {1966},
	month = {1966},
	pages = {97-119},
	keywords = {Animals, Blood Circulation, Homeostasis, Humans, Physical Exertion},
	issn = {0039-3959},
	author = {Zamfirescu, N R}
}
