On the role of self-recognition in T cell responses to foreign antigen

The key role of the thymus in shaping the peripheral T cell receptor (TCR) repertoire has been appreciated for nearly a quarter of a century. For most of that time, a single model has dominated thinking about the physiological role of the positive selection process mediated by TCR recognition of self-peptides and major histocompatibility complex (MHC) molecules. This developmental filter was believed to populate secondary lymphoid tissues with T cells bearing receptors best able to recognize unknown foreign peptides associated with the particular allelic forms of the MHC molecules present in an individual. More recently, self-recognition has been suggested to regulate the viability of naive T cells. Here we focus on new results indicating that a critical contribution of positive selection to host defense is insuring that each peripheral T cell can use self-recognition to (i) enhance TCR signaling sensitivity upon foreign antigen recognition and (ii) augment the clonal expansion that accompanies limiting foreign antigen display at early points in an infectious process. We also detail new insights into the intracellular signaling circuitry that underlies the effective discrimination between low- and high-quality ligands of the TCR and speculate on how this design might facilitate an additional contribution of self-recognition to T cell activation in the presence of foreign stimuli.