GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE305nnn/GSE305926/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE305926GEOGSEfalseEpigenetic 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.2026/08/10GSE305926GSM9188067GSM9188089GSM9188068GSM9188069GSM9188081GSM9188082GSM9188060GSM9188061GSM9188083GSM9188084GSM9188062GSM9188085GSM9188063GSM9188064GSM9188086GSM9188087GSM9188065GSM9188088GSM9188066GSM9188080GSM9188056GSM9188078GSM9188079GSM9188057GSM9188058GSM9188059GSM9188070GSM9188092GSM9188093GSM9188071GSM9188094GSM9188072GSM9188073GSM9188051GSM9188095GSM9188096GSM9188074GSM9188052GSM9188053GSM9188097GSM9188075GSM9188098GSM9188076GSM9188054GSM9188077GSM9188055GSM9188090GSM918809113112305926Mus musculus