• lab members in Star Wars costumes
  • 2019 Group Picture

What We Do

The Sharpe laboratory investigates T cell costimulatory pathways and their immunoregulatory functions. We focus on the roles of these pathways in regulating pathogenic and protective immune responses needed for the induction and maintenance of T cell tolerance and the prevention of autoimmunity, as well as effective antimicrobial and antitumor immunity.

We are also involved in studies aimed at translating the fundamental understanding of T cell costimulation into new therapies for autoimmune diseases, chronic viral infections, and cancer. Manipulation of T cell costimulatory pathways is of great therapeutic interest as it may provide a means to enhance immune responses to promote anti-microbial and tumor immunity, or to terminate immune responses to control autoimmune diseases and achieve tolerance for organ transplantation.

Recent Publications

Regulatory T cells in dominant immunologic tolerance

Georgiev P, Benamar M, Han SJ, Haigis MC, Sharpe AH, Chatila TA. Regulatory T cells in dominant immunologic tolerance. J Allergy Clin Immunol. 2024;153 (1) :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.
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X-CHIME enables combinatorial, inducible, lineage-specific and sequential knockout of genes in the immune system

LaFleur MW, Lemmen AM, Streeter ISL, Nguyen TH, Milling LE, Derosia NM, Hoffman ZM, Gillis JE, Tjokrosurjo Q, Markson SC, et al. X-CHIME enables combinatorial, inducible, lineage-specific and sequential knockout of genes in the immune system. Nat Immunol. 2024;25 (1) :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.
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Regulatory T cells in skin mediate immune privilege of the hair follicle stem cell niche

Cohen JN, Gouirand V, Macon CE, Lowe MM, Boothby IC, Moreau JM, Gratz IK, Stoecklinger A, Weaver CT, Sharpe AH, et al. Regulatory T cells in skin mediate immune privilege of the hair follicle stem cell niche. Sci Immunol. 2024;9 (91) :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.
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Tracking tumor-specific CD8 T cell responses

Burke KP, Markson SC, Sharpe AH. Tracking tumor-specific CD8 T cell responses. Trends Immunol. 2023;44 (5) :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.
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Uncoupled glycerol-3-phosphate shuttle in kidney cancer reveals that cytosolic GPD is essential to support lipid synthesis

Yao C-H, Park JS, Kurmi K, Hu S-H, Notarangelo G, Crowley J, Jacobson H, Hui S, Sharpe AH, Haigis MC. Uncoupled glycerol-3-phosphate shuttle in kidney cancer reveals that cytosolic GPD is essential to support lipid synthesis. Mol Cell. 2023;83 (8) :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.
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