Functional heterogeneity and plasticity in naïve CD8 T cells drive superior effector and memory responses

ABSTRACT While significant progress has been made in defining subsets among antigen-experienced CD8 T cells, the heterogeneity of naïve CD8 T cells remains poorly understood. Here, we identify naïve CD8 T cell subsets with superior persistence and an enhanced capacity to generate effector and memory cells, leading to more effective protection. These high-quality naïve CD8 T cells are marked by IL-18Rα, CD73, and CXCR3, and functionally less potent naïve CD8 T cells can convert into these superior subsets. Their enhanced response to infections is driven by better survival of the progeny effector cells during the T cell expansion phase. This improved survival is mediated by increased Ly6C2 expression on effector cells derived from these high-quality naïve cells. Collectively, our findings reveal functional heterogeneity and plasticity among naïve CD8 T cells and uncover a mechanism by which high-quality naïve subsets drive robust CD8 T cell responses, providing a previously unrecognized layer of immune regulation. SUMMARY Our study reveals functional heterogeneity and plasticity within naïve CD8 T cells, identifying high-quality subsets that can emerge from less potent cells and drive superior immune responses through enhanced survival of effector progeny.