Epigenetic training licenses naïve CD8+ T cell metabolic fitness and function.

Naïve T cells maintain quiescence yet must respond rapidly to antigens, but how they prime this capacity is unclear. We identify histone variant H2A.Z as a key regulator of an epigenetic training program that licenses quiescent naïve CD8+ T cells for future activation. H2A.Z deficiency disrupts naïve T cell homeostasis and effector responses. Multiomics reveals that H2A.Z is selectively deposited at oxidative phosphorylation (OXPHOS) gene promoters in quiescent naïve CD8+ T cells, priming the chromatin for rapid transcriptional induction. This training is developmentally instructed by tonic interleukin-7 (IL-7) signaling and regulated by transcription factor GABPα. Age-related decline in IL-7 signaling reduces H2A.Z occupancy and impairs T cell activation, while IL-7 supplementation or enforced H2A.Z expression rescues this defect. H2A.Z overexpression also enhances chimeric antigen receptor T cell stemness and antitumor efficacy. Our work defines an IL-7R-GABPα-H2A.Z-OXPHOS axis that epigenetically establishes metabolic and functional fitness in quiescent T cells, offering insights for immunotherapy targeting ageing and tumors.