GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE305nnn/GSE305895/primaryOK200GenomicsMus musculusGenome binding/occupancy profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE305895GEOGSEfalseEpigenetic training licenses naïve CD8⁺ T cell metabolic fitness and functionNaïve 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. Multi-omics reveals that H2A.Z is selectively deposited at OXPHOS gene promoters in quiescent naïve CD8+ T cells, priming the chromatin for rapid transcriptional induction. This training is developmentally instructed by tonic 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 CAR-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.2026/08/10GSE305895GSM9187143GSM9187132GSM9187122GSM9187144GSM9187133GSM9187134GSM9187123GSM9187124GSM9187135GSM9187125GSM9187136GSM9187126GSM9187137GSM9187138GSM9187127GSM9187128GSM9187139GSM9187140GSM9187141GSM9187130GSM9187131GSM9187142GSM918712924247305895Mus musculus