Antigen specificity shapes distinct aging trajectories of memory CD8⁺ T cells

Ines Sturmlechner (), Abhinav Jain, Bin Hu, Rohit R. Jadhav, Wenqiang Cao, Hirohisa Okuyama, Lu Tian, Cornelia M. Weyand and Jörg J. Goronzy ()
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Ines Sturmlechner: Mayo Clinic
Abhinav Jain: Mayo Clinic
Bin Hu: Stanford University
Rohit R. Jadhav: Mayo Clinic
Wenqiang Cao: Mayo Clinic
Hirohisa Okuyama: Mayo Clinic
Lu Tian: Stanford University
Cornelia M. Weyand: Mayo Clinic
Jörg J. Goronzy: Mayo Clinic

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Memory T cells are a highly heterogeneous collection of antigen-experienced cells that undergo dynamic adaptations upon antigen re-encounter and environmental signals. This heterogeneity hinders studies on memory T cell durability and age-related dysfunction. Using chronic Epstein-Barr virus (EBV) infection and barcode-enabled antigen tracing, we assess the influence of age on memory states at the level of single antigen-specific CD8+ T cells. In young adults ( 65-years), antigen-specific cells show largely distinct phenotypic and transcriptomic aging trajectories. Common to many albeit not all antigen-specific populations are maintained TCR diversity, gained natural killer cell-like, innate signatures and lost stem-like features while no evidence is seen for cellular senescence or exhaustion. TCR avidity contributes to these phenotypic differences and aging-related changes. Collectively, our data uncover divergent antigen-guided aging shifts in memory T cell phenotypes, which are informative for antigen selection in optimizing vaccine design and adoptive T cell therapy.

Date: 2025
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DOI: 10.1038/s41467-025-61627-y

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