In Silico and In Vitro Studies of T Cell Signaling

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Elimination of Listeria monocytogenes requires the recognition of L monocytogenes antigens by T cells. T cell activation is initiated by the binding of the T cell receptor (TCP) on the T cell surface to cognate pMHC ligands on antigen presenting cells (APCs). While most work on T cell activation has focused on the interaction of the TCR with the antigenic peptide bound to MHC, recent work demonstrates that nonantigenic, endogenous self peptides play important roles in cooperating with antigenic peptides to allow for sufficient signaling to activate T cells. This suggests that variability of endogenous peptides could play a critical role in determining the outcome of an infection. In addition, the role of endogenous peptides suggests new ways to think about peptide antagonism, a phenomenon that is still unexplained. Here we propose to use mathematical modeling with genetic and biochemical experiments to lend new insights into how endogenous peptides contribute to the initial signaling events that trigger T cell activation. We propose to examine the role of endogenous pMHC ligands in mediating signaling during the recognition of L. monocytogenes. We also propose to determine the interplay between TCR signaling stimulated by endogenous, agonist, and antagonist ligands with a view toward determining the mechanism underlying antagonism in vitro. Lastly, we hope to for the first time try and establish a model for studying antigenic antagonism in vivo. We believe that these studies will lead to a better understanding of how the immune system sense and eliminates pathogens.