In Silico and In Vitro Studies of T Cell Signaling

Elimination of Listeria monocytogenes requires the recognition of L monocytogenes antigens by T cells. Tcell activation is initiated by the binding of the T cell receptor (TCP) on the T cell surface to cognate pMHCligands on antigen presenting cells (APCs). While most work on T cell activation has focused on theinteraction 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 forsufficient signaling to activate T cells. This suggests that variability of endogenous peptides could play acritical role in determining the outcome of an infection. In addition, the role of endogenous peptides suggestsnew ways to think about peptide antagonism, a phenomenon that is still unexplained.<P>Here we propose touse mathematical modeling with genetic and biochemical experiments to lend new insights into howendogenous peptides contribute to the initial signaling events that trigger T cell activation. We propose toexamine 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 byendogenous, agonist, and antagonist ligands with a view toward determining the mechanism underlyingantagonism in vitro. <P>Lastly, we hope to for the first time try and establish a model for studying antigenicantagonism in vivo. We believe that these studies will lead to a better understanding of how the immunesystem sense and eliminates pathogens.