Calibrating T cell responsiveness through interactions with self

During an immune response, T cells face one of the most consequential decisions of their lifespan upon recognition of a ligand they have not previously encountered: whether to exit the naive basal state, undergo clonal expansion and acquire effector functions. This process is often portrayed as a binary switch, in which naive cells from a highly diverse repertoire transition from an 'off' state to an 'on' state. However, this digital view overlooks the crucial prior information that T cells integrate through T cell receptor (TCR) interactions with self-peptide-MHC (self-pMHC). During thymic selection, immature T cells encounter a unique self-pMHC ligandome that shapes their development. After maturation, naive T cells continue to engage self-ligands as they patrol secondary lymphoid organs. Here we review evidence that these encounters with self-peptides are not only essential for T cell survival but also have lasting consequences that dynamically tune T cell function when called into action. The naive off state, therefore, is neither fixed nor functionally neutral. We argue that a deeper understanding of an individual's self-peptide repertoire is crucial for deciphering TCR self and non-self discrimination and for effectively harnessing T cell responses to foreign antigens.