T Cell Differentiation and Repertoire Selection

Division Of Basic Sciences - Nci

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Abstract

Thymocytes signaled by T-cell receptors (TCR) migrate through the thymus and differentiate into different T-lineages, but T-lineage determination remains incompletely understood. Here, we report that encoding CD8 coreceptors in both Cd4 and Cd8 gene loci generates all possible CD8 T-lineages based simply on MHC-I TCR signaling duration. Because Cd4-encoded CD8 coreceptors promote prolonged signaling and helper-fate, while Cd8-encoded CD8 coreceptors promote disrupted signaling and cytotoxic-fate, coreceptor genes determine CD8 T-lineage fates by regulating signaling duration. Strikingly, we discovered that thymic self-peptides also shape CD8 T-lineage fates by affecting signaling duration. Self-peptides expressed exclusively in the cortex induce TCR signaling that becomes disrupted during thymocyte migration and generate only cytotoxic CD8 T-cells, whereas thymic self-peptides expressed throughout the thymus induce prolonged or recurrent TCR signaling which generates helper or innate memory CD8 T-cells. This work reveals how unrelated aspects of positive selection converge to specify CD8 T cell fates.