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Thymic age and peripheral residence time determine anti-tumor competence of CD8+ T cells

ABSTRACT: The developmental timing of T cell generation imprints durable functional programs, yet how this shapes anti-tumor immunity remains unclear. Here, we combine genetic fate mapping with functional assays to dissect how thymic age and peripheral residency regulate CD8⁺ T cell behaviour 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 post-thymic remodelling. 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 anti-tumor immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE339309 | GEO | 2026/09/01

REPOSITORIES: GEO

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