The Sharpe laboratory investigates T cell costimulatory pathways and their immunoregulatory functions. We have discovered T cell costimulatory pathways and elucidated the functions of B7-1 and B7-2, CTLA-4, ICOS, PD-1 and PD-1 ligands. The laboratory uses genetic approaches to determine the obligatory functions of T cell costimulatory pathways through the generation and analyses of transgenic and knockout mice in mouse models of autoimmunity, infectious diseases, and tumor immunity. In addition, we are involved in studies aimed at translating fundamental understanding of T cell costimulation into new therapies for autoimmune diseases, chronic viral infections, and cancer. We study the function of coinhibitory pathways in human tissues using histologic, immunologic, transcriptomic and proteomic approaches. Current areas of interest in the lab include defining roles of coinhibitory pathways in regulating the induction and maintenance of T cell tolerance and effective antimicrobial and antitumor immunity.
A major focus of the lab is to determine how coinhibitory receptors/ligands on different cell types (hematopoietic, stromal, and epithelial) participate in the regulation of tolerance in lymphoid organs and in tissues. For example, we are investigating how CTLA-4 and PD-1 control regulatory T cell biology (regulatory T cell development/induction, maintenance, and function). Using a mouse model of multiple sclerosis (experimental autoimmune encephalitis, EAE) we have shown that the suppressive capacity T-regulatory cells is increased following conditional deletion of CTLA-4 on T-regulatory cells in adult mice. We are currently dissecting the roles of the PD-L1: PD-1 axis on specific cell types in controlling tolerance in EAE and non-obese diabetes models.
Checkpoint blockade using anti-PD-1 and anti-CTLA-4 antibodies has lead to remarkable, durable clinical responses in multiple cancer types. Despite these impressive clinical benefits, the basic mechanism by which PD-1 blockade induces tumor regression is not clear. We are investigating how PD-1 contributes to the immunosuppressive tumor microenvironment by analyzing the functions of PD-1 on different cell types within the tumor using immunologic, transcriptional, and phosphoproteomic approaches. In complementary studies, we are investigating PD-1 ligands, particularly PD-L1, by comparing PD-L1 functions on tumor cells, hematopoietic and non hematopoietic cells. In addition, we are investigating synergies between the PD-1 pathway and other immunoinhibitory pathways as well as other therapies such as Braf /Mek inhibitors.
Coinhibitory Basic Research
There are many T costimulatory and coinhibitory pathways and we are interesting in understanding their unique and synergistic functions. We have developed both global and conditional knockout mice for many coinhibitory receptors and are using these tools to determine the roles of these molecules on specific cell types at different stages of immune responses. Further, transcriptional analyses of selective ablation of coinhibitory receptors have revealed mechanisms by which coinhibitory receptors affect different immune cell types, and have identified novel coinhibitory receptors. One major project involves elucidating how CTLA-4 and PD-1 control B cells, T follicular helper cells, and T follicular regulatory cells in the germinal center and regulate antibody production.
We have a great interest in translating our findings on coinhibitory receptors to understanding human biology and influencing therapies. One active project involves the use of the cell surface marker CD39 as a marker of T cell exhaustion in the context of chronic viral infections such as HIV and HCV, as well as human tumors. We are also privileged to work with our clinical collaborators to study immune cells from human tumors transcriptionally and functionally.
Work in the lab on the role of coinhibitory receptors in viral immunity has centered on the LCMV Armstrong, LCMV Clone 13, and Influenza viruses. Our work on these viruses has focused around the role of the PD-1 pathway and other coinhibitory molecules identified using an shRNA screen on CD8 T cell memory formation.