Authors
Yuanqin Yang, Yunyi Wang, Amanda Wicki, Qianpeng Li, Chunrun Qu, Brian Debo, Berna Bou Tayeh, Tingyu Wen, Hui Huang, Amir Hosseini, Vinnycius Pereira Almeida, Carol S Leung, Georg A Holländer, Benoit Van den Eynde, Yang Shi
Published in
Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 39. Pages e2612774123. Sep 29, 2026. Epub Sep 21, 2026.
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.
PMID:
42766737
Bibliographic data and abstract were imported from PubMed on 22 Sep 2026.
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