Exhausted T cells (TEX) in cancer and chronic viral infections undergo metabolic and epigenetic remodeling, impairing their protective capabilities. However, the impact of nutrient metabolism on epigenetic modifications that control TEX differentiation remains unclear. We showed that TEX cells shifted from acetate to citrate metabolism by downregulating acetyl-CoA synthetase 2 (ACSS2) while maintaining ATP-citrate lyase (ACLY) activity. This metabolic switch increased 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 prevented TEX differentiation and enhanced tumor-specific T cell responses. These findings unveiled a nutrient-instructed histone code governing CD8 + T cell differentiation, with implications for metabolic- and epigenetic-based T cell therapies.

中文翻译：

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营养驱动的组蛋白密码决定耗竭的 CD8 + T 细胞命运


癌症和慢性病毒感染中的耗竭 T 细胞 （TEX） 经历代谢和表观遗传重塑，损害其保护能力。然而，营养代谢对控制 TEX 分化的表观遗传修饰的影响仍不清楚。我们发现，TEX 细胞通过下调乙酰辅酶 A 合成酶 2 （ACSS2） 从乙酸盐代谢转变为柠檬酸盐代谢，同时保持 ATP-柠檬酸裂解酶 （ACLY） 活性。这种代谢转换增加了 TEX 特征基因处柠檬酸盐依赖性组蛋白乙酰化（由组蛋白乙酰转移酶 KAT2A-ACLY 相互作用介导），同时减少了依赖于 p300-ACSS2 复合物、效应细胞和记忆 T 细胞基因的乙酸盐依赖性组蛋白乙酰化。核 ACSS2 过表达或 ACLY 抑制阻止了 TEX 分化并增强了肿瘤特异性 T 细胞反应。这些发现揭示了一种由营养指导的控制 CD8 + T 细胞分化的组蛋白密码，对基于代谢和表观遗传学的 T 细胞疗法具有意义。