T Cell Activation in Response to Pathogens

The orchestrators of the adaptive immune response to pathogens are a class of cells called T lymphocytes (T cells). They have evolved to deal with pathogens that have invaded cells. Specialized cells, called antigen presenting cells (APCs), display molecular signatures of the pathogen on their surface. These molecules are comprised of peptides (p) derived from the pathogen’s proteins bound to protein products of the majorhistocompatibility (MHC) gene complex. Interactions of the T cell receptor expressed on the surface of T cells with these pMHC molecules predicates T cell activation. We are interested in understanding the factors that determine T cell activation. The specific issues that we study include: 1] How T cells detect minute amounts of pathogen-derived pMHC molecules in a sea of endogenous pMHC molecules expressed on APC surfaces? 2] How do downstream signaling processes propagate and regulate membrane-proximal signals? 3] How does spatial organization of signaling components regulate T cell activation? 4] How do T cells scan for APCs bearing molecular signatures of antigen in lymphoid tissue?

We study these issues using sophisticated computer simulation based on statistical mechanics as well as analytical approximations, the latter efforts being very important for deep insights. These theoretical and computational studies are carried out in close collaboration with collaborators who are leading immunologists who develop and apply genetic, biochemical, and imaging experiments to address the same questions.