Unraveling CD8 lineage decisions reveals that functionally distinct CD8⁺ T cells are selected by different MHC-I...

Thymocytes signaled by T cell antigen receptors to undergo positive selection acquire different functional fates while migrating through the thymus, but how this occurs remains uncertain. We now report that encoding CD8 co-receptors in both Cd4 and Cd8 gene loci modulates major histocompatibility complex (MHC-I) class I T cell antigen receptor signaling duration to generate all potential CD8⁺ T cell subsets. Strikingly, such mice revealed that functionally different CD8⁺ T cells are selected by different MHC-I thymic peptides. Thymocytes signaled by β5t-peptides produced by thymoproteasomes exclusively expressed in the thymic cortex invariably become cytotoxic CD8⁺ T cells indicating their signaling ceases when thymocytes leave the cortex; whereas thymocytes signaled by nonβ5t-peptides expressed throughout the thymus become either helper or innate memory CD8⁺ T cells because their signaling persists or recurs outside the cortex. Thus, it is because of their different thymic distributions that different MHC-I peptides select functionally different CD8⁺ T cells, integrating peptide specificity and CD8⁺ T cell function during positive selection and thymocyte migration.