Molecular drivers of effective T cell receptor signaling

TCR recognition of peptide + MHC class I complexes (pMHCI) is central to CD8+ T cell function. It is clear that the nature of the TCR-pMHCI interaction, typically through alterations in the strength of that interaction, is central to the signal transduced and subsequent activation of the T cell, but the mechanism by which the recognition event translates into the signaling event is poorly understood. My laboratory has identified the first endogenously-derived TCR that docks on its cognate viral peptide+MHCI in a reversed orientation compared to all other CD8+ T cells (Gras et al, 2016, Immunity). We have shown that the altered positioning of the TCR over the pMHCI negatively impacts the T cell’s ability to be activated, independently of the interaction strength. Using these unique TCR tools identified by my laboratory, as well as cutting edge techniques including single cell analyses, in vivo retroviral transduction, and high resolution imaging approaches, we aim to elucidate the molecular mechanisms underpinning effective TCR signaling. This work will significantly advance our fundamental understanding of the key drivers of effective T cell activation and have implications for the many clinical interventions that rely on augmentation or suppression of T cell activation.