Thymic age and peripheral residence time determine antitumor competence of CD8+ T cells.
TL;DR
These findings establish developmental imprinting as an important determinant of CD8+ T cell heterogeneity and identify CXCR3+IL-18Rα+ CD8+ T cells as key effectors for antitumor immunity.
Abstract
The developmental timing of T cell generation imprints durable functional programs, yet how this shapes antitumor immunity remains unclear. Here, we combine genetic fate mapping with functional assays to dissect how thymic age and peripheral residency regulate CD8+ T cell behavior within the same host. We find that, compared with adulthood-derived CD8+ T cells, the adolescent-derived counterparts consistently exhibit enhanced tumor infiltration, increased effector cytokine production, and superior proliferative fitness. Transcriptomic and phenotypic profiling identify a CXCR3+IL-18Rα+ subset preferentially enriched among adolescent-derived T cells that shares core virtual memory-like features and displays elevated cytotoxic potential. Mechanistically, thymic origin timing and time spent in the periphery independently regulate the abundance and activity of this subset, revealing a two-tier control comprising developmental bias and postthymic remodeling. Functionally, CXCR3+IL-18Rα+ CD8+ T cells mediate potent tumor killing and confer robust therapeutic benefit in adoptive transfer models. Together, these findings establish developmental imprinting as an important determinant of CD8+ T cell heterogeneity and identify CXCR3+IL-18Rα+ CD8+ T cells as key effectors for antitumor immunity.