T cell antigen recognition is the critical initiating step for effective cellular immunity. Therefore, understanding the mechanisms by which T cells are triggered is important if we are to rationally optimize the adaptive immune response to cancer and viral infections. The activation steps that occur in response to strong antigens have been described, yet it is still unclear how TCRs interact with weaker stimuli. For example, peptides that form less stable antigenic complexes are prevalent and encountered by T cells during surveillance of self, tumors, and chronic infections. Our goal is to identify the mechanisms of TCR triggering in response to less stable pMHC complexes.
The specific aims are designed to address the following questions: How do less stable pMHC complexes trigger T cell responses? Do less stable pMHC complexes activate SHP-1 as a negative regulator of T cell effector functions? Can we optimize anti-viral T cell responses by targeting SHP-1? What are the TCR kinetics with less stable pMHC complexes and does the pMHC complex decay during antigen recognition? Answers to these questions will broaden our overall understanding of T cell activation and specifically provide methods for optimizing response to less stable peptides typical of tumor and viral escape antigens.
