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

FoxP3 and Ezh2 regulate Tfr cell suppressive function and transcriptional program

Hou S, Clement RL, Diallo A, Blazar BR, Rudensky AY, Sharpe AH, Sage PT. FoxP3 and Ezh2 regulate Tfr cell suppressive function and transcriptional program. J Exp Med. 2019;216 (3) :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.
Read more

Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade

Miller BC, Sen DR, Abosy RA, Bi K, Virkud YV, LaFleur MW, Yates KB, Rodig SK, Sharpe AH, Haining NW, et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol. 2019;20 (3).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 ‘progenitor exhausted’ cells that retain polyfunctionality, persist long term and differentiate into ‘terminally exhausted’ 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.
Read more

A CRISPR-Cas9 delivery system for in vivo screening of genes in the immune system

LaFleur MW, Nguyen TH, Coxe MA, Yates KB, Trombley JD, Weiss SA, Brown FD, Gillis JE, Coxe DJ, Deonch JG, et al. A CRISPR-Cas9 delivery system for in vivo screening of genes in the immune system. Nat Commun. 2019;10 (1668).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.
Read more

CD160 Stimulates CD8+ T Cell Responses and Is Required for Optimal Protective Immunity to Listeria monocytogenes

Tan CL, Peluso MJ, Drivjers JM, Mera CM, Grande SM, Brown KE, Godec J, Freeman GJ, Sharpe AH. CD160 Stimulates CD8+ T Cell Responses and Is Required for Optimal Protective Immunity to Listeria monocytogenes. ImmunoHorizons. 2018;2 (7) :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+ T cell effector functions needed for optimal clearance of oral Listeria monocytogenes infection. CD160−/− mice did not clear oral L. monocytogenes as efficiently as wild type (WT) littermates. WT RAG−/− and CD160−/− RAG−/− mice similarly cleared L. monocytogenes, indicating that CD160 on NK cells does not contribute to impaired L. monocytogenes clearance. Defective L. monocytogenes clearance is due to compromised intraepithelial lymphocytes and CD8+ T cell functions. There was a reduction in the frequencies of granzyme B–expressing intraepithelial lymphocytes in L. monocytogenes–infected CD160−/−mice as compared with WT littermate controls. Similarly, the frequencies of granzyme B–expressing splenic CD8+ T cells and IFN-γ and TNF-α double-producer CD8+ T cells were significantly reduced in L. monocytogenes–infected CD160−/− mice compared with WT littermates. Adoptive transfer studies showed that RAG−/− recipients receiving CD160−/− CD8+ T cells had a higher mortality, exhibited more weight loss, and had a higher bacterial burden compared with RAG−/− recipients receiving WT CD8+ T cells. These findings demonstrate that CD160 provides costimulatory signals to CD8+ T cells needed for optimal CD8+ T cell responses and protective immunity during an acute mucosal bacterial infection.
Read more

Inhibitors of the PD-1 Pathway in Tumor Therapy

LaFleur MW, Muroyama Y, Drake CG, Sharpe AH. Inhibitors of the PD-1 Pathway in Tumor Therapy. J Immunol. 2018;200 (2) :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.
Read more