Intrinsic CD4(+) T cell sensitivity and response to pathogen are set and sustained by avidity for thymic and peripheral self-pMHC

T cell receptor (TCR) interactions with self-peptide-major histocompatibility complex (pMHC) are crucial to T cell development, but their role in peripheral T cell responses remains unclear. Specific and nonspecific stimulation of Listeria-specific LLO56 and LLO118 TCR transgenic T cells elicited distinct interleukin 2 (IL-2) and phospho-ERK responses, the strength of which was set in the thymus and maintained in the periphery in proportion to TCR-self-pMHC avidity. Withdrawal of self-pMHC markedly compromised LLO56 expansion to Listeria in vivo. Despite their markedly different self-reactivities, LLO56 and LLO118 bound cognate-pMHC with identical affinities, challenging associations made between these parameters. Our findings highlight a crucial role for selecting ligands encountered during thymic education in determining the intrinsic functionality of CD4(+) T cells.