Nutrient-driven histone code determines exhausted CD8+ T cell fates [RNA-seq]. Nutrient-driven histone code determines exhausted CD8+ T cell fates [RNA-seq]

To investigate the role of ACSS2NLS in the regulation of CD8+ T cell responses in B16-GP33 tumor model Exhausted T cells (TEX) in cancer and chronic viral infections undergo metabolic and epigenetic remodeling, impairing protective capabilities. However, the impact of nutrient metabolism on epigenetic modifications that control TEX differentiation remains unclear. Our study reveals that TEX cells shift from acetate to citrate metabolism by downregulating acetyl-CoA synthetase 2 (ACSS2) while maintaining ATP-citrate lyase (ACLY) activity. This metabolic switch increases citrate-dependent histone acetylation, mediated by histone acetyltransferase KAT2A-ACLY interactions, at TEX signature-genes while reducing acetate-dependent histone acetylation, dependent on p300-ACSS2 complexes, at effector and memory T cell genes. Nuclear ACSS2 overexpression or ACLY inhibition prevents TEX differentiation and enhances tumor-specific T cell responses. These findings unveil a nutrient-driven histone code governing CD8+ T cell differentiation, with implications for metabolic- and epigenetic-based T cell therapies Overall design: RNA-seq gene expression profiling analysis for EV and ACSS2NLS TILs in B16-GP33 tumor at day 21 post tumor implantation

为探究核定位乙酰辅酶A合成酶2（ACSS2NLS）在B16-GP33肿瘤模型中对CD8+ T细胞应答的调控作用。癌症与慢性病毒感染中的耗竭性T细胞（Exhausted T cells，TEX）会发生代谢与表观遗传重塑，使其机体防护能力受损。然而，营养代谢对调控TEX分化的表观遗传修饰的具体影响仍不明晰。本研究揭示，TEX细胞通过下调乙酰辅酶A合成酶2（acetyl-CoA synthetase 2，ACSS2）的表达，同时维持ATP-柠檬酸裂解酶（ATP-citrate lyase，ACLY）的活性，完成从乙酸代谢向柠檬酸代谢的代谢转换。这种代谢转换可增强TEX特征基因位点处依赖柠檬酸的组蛋白乙酰化修饰，该修饰由组蛋白乙酰转移酶KAT2A与ACLY的相互作用所介导；同时会降低效应T细胞与记忆T细胞基因位点处依赖乙酸的组蛋白乙酰化修饰，该修饰依赖于p300-ACSS2复合物。过表达核定位ACSS2或抑制ACLY活性，可阻断TEX分化进程并增强肿瘤特异性T细胞应答。本研究结果揭示了一种由营养物质驱动的、调控CD8+ T细胞分化的组蛋白密码，为基于代谢与表观遗传的T细胞治疗提供了理论依据。实验设计：对肿瘤接种后第21天的B16-GP33肿瘤模型中的EV组与ACSS2NLS组肿瘤浸润淋巴细胞（tumor-infiltrating lymphocytes，TILs）开展RNA测序基因表达谱分析。