The major interest of the Sharpe laboratory is to study functions of T cell costimulatory pathways and their immunoregulatory roles in controlling the balance between T cell activation and tolerance. Costimulation is of therapeutic interest because manipulation of T cell costimulatory pathways may provide a means either to enhance immune responses (to promote anti-microbial or tumor immunity) or terminate immune responses (to control autoimmune diseases or achieve tolerance for tissue transplantation).

The Sharpe laboratory has used genetic approaches to determine the obligatory functions of T cell costimulatory pathways. This research has provided novel insights and revealed unexpected functions of costimulatory pathways in the B7:CD28 family of costimulatory For example, we have found a critical role for the CD28 homolog ICOS in regulating T cell dependent B cell responses, and the development of several CD4 T cell lineages. Our studies in the PD-1:PD-1 ligand pathway have shown that PD-L1 and PD-L2 are ligands for PD-1 and can inhibit naïve and effector T cells. Further work demonstrated a novel role for PD-L1 on parenchymal cells in regulating self-reactive T cells. Additional studies indicate that PD-1 and PD-L1 inhibit T cell function during chronic viral infection and blockade of this pathway can restore function of “exhausted” T cells. These findings have revealed a new therapeutic strategy for chronic viral infection. We also have identified B7-1 and PD-L1 as binding partners and shown that their interaction inhibits T cell responses. The identification of this new pathway give increased significance to B7-1 and PD-L1 on T cells, and compels a reassessment of pathways in the B7:C28 family in regulating T cell activation and tolerance.

Current areas of interest in the lab include defining roles of costimulatory and coinhibitory pathways in regulating the balance between pathogenic and protective T cell responses in mouse models of infection, autoimmunity, and cancer. We are using conditional gene targeting approaches to define the function of coinhibitory receptors on regulatory, effector and memory T cells (as well as other cell types). We also are defining unique and synergistic functions of costimulatory and coinhibitory pathways (e.g., PD-1, CTLA-4, LAG3, TIGIT). Finally we are beginning to examine how costimulatory and coinhibitory functions in T cells change with age.