Science Advances, 18 September, 2026, DOI：https://doi.org/10.1126/sciadv.aee8251

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

Mengjie Lv, Jiyu Ding, Haizhen Long, Qian Chai, Lili Xu, Caiwei Jin, Wei Liang, Liwei Zhang, Bangmin Zhang, Zhihan Lv, Jicheng Zhao, Guohong Li, and Mingzhao Zhu

Abstract

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.

Article link：https://www.science.org/doi/10.1126/sciadv.aee8251