TCR avidity for thymic and peripheral self peptide-MHC sets and sustains intrinsic CD4+ T cell sensitivity (P1170)

Abstract TCR interactions with pMHC are crucial to T cell development and function. It is not known how the strength of the positively selecting signal impacts peripheral T cell function. To pursue this issue, we utilized the LLO56 and LLO118 TCR transgenic mice, each of which bears CD4+ T cells that recognize the same epitope from Listeriolysin O. During in vivo responses to L. monocytogenes, LLO118 T cells expand better upon primary challenge, whereas LLO56 prevails upon rechallenge. Surprisingly, naive LLO56 T cells showed stronger IL-2 responses than LLO118 to nonspecific in vitro stimulation, associated with greater ERK activation and higher basal phospho-TCRζ levels. The greater basal TCRζ phosphorylation, along with higher CD5 expression, suggested that LLO56 has a higher avidity for self-pMHC, possibly underlying its higher sensitivity. Indeed, the respective sensitivities of LLO56 and LLO118 cells emerged as they matured into CD4SP thymocytes after positive selection, during which LLO56 thymocytes received a stronger signal from selecting self-pMHC. Peripheral self-pMHC was required to actively maintain mature LLO56 and LLO118 T cell sensitivity, as transfer of these cells into MHC II-/- mice rendered them similarly unresponsive to stimulation. In summary, our data demonstrate unanticipated roles for TCR:self-pMHC avidity in establishing T cell sensitivity centrally, sustaining it in the periphery, and affecting CD4+ T cell responses to pathogens.