Aging trajectories of memory CD8 ⁺ T cells differ by their antigen specificity

Memory T cells are a highly dynamic and heterogeneous population that is maintained by cytokine-driven homeostatic proliferation interspersed with episodes of antigen-mediated expansion and contraction which affect their functional state and their durability. This heterogeneity complicates studies on the impact of aging on global human memory cells, specifically, it is unclear how aging drives memory T cell dysfunction. Here, we used chronic infection with Epstein-Barr virus (EBV) to assess the influence of age on memory states at the level of antigen-specific CD8 ⁺ T cells. We find that in young adults (<40 years), EBV-specific CD8 ⁺ T cells assume preferred differentiation states depending on their peptide specificity. By age >65-years, different T cell specificities had undergone largely distinct aging trajectories, which had in common a loss in adaptive and a gain in innate immunity signatures. No evidence was seen for cellular senescence or exhaustion. While naïve/stem-like EBV-specific T cells disappeared with age, T cell diversity of EBV-specific memory cells did not change or even increased. In summary, by controlling for antigen specificity we uncover age-associated shifts in gene expression and TCR diversity that have implications for optimizing vaccination strategies and adoptive T cell therapy.