据介绍，耗竭的T细胞（TEX）在癌症和慢性病毒感染中经历代谢和表观遗传重塑，损害了它们的保护能力。然而，营养代谢对控制TEX分化的表观遗传修饰的影响尚不清楚。
研究人员发现，TEX细胞通过下调乙酰辅酶a合成酶2 （ACSS2）而维持ATP -柠檬酸裂解酶（ACLY）活性，从醋酸盐代谢转变为柠檬酸盐代谢。这种代谢开关增加了TEX特征基因上，由组蛋白乙酰转移酶KAT2A-ACLY相互作用介导的柠檬酸盐依赖性组蛋白乙酰化，同时减少了效应和记忆T细胞基因上，依赖于p300-ACSS2复合物的醋酸盐依赖性组蛋白乙酰化。
核ACSS2过表达或ACLY抑制阻止TEX分化，和增强肿瘤特异性T细胞反应。这些发现揭示了一种营养指导的组蛋白编码控制CD8+ T细胞分化，这对基于代谢和表观遗传学的T细胞治疗具有重要意义。
附：英文原文
Title: Nutrient-driven histone code determines exhausted CD8+ T cell fates
Author: Shixin Ma, Michael S. Dahabieh, Thomas H. Mann, Steven Zhao, Bryan McDonald, Won-Suk Song, H. Kay Chung, Yagmur Farsakoglu, Lizmarie Garcia-Rivera, Filipe Araujo Hoffmann, Shihao Xu, Victor Y. Du, Dan Chen, Jesse Furgiuele, Michael LaPorta, Emily Jacobs, Lisa M. DeCamp, Brandon M. Oswald, Ryan D. Sheldon, Abigail E. Ellis, Longwei Liu, Peixiang He, Yingxiao Wang, Cholsoon Jang, Russell G. Jones, Susan M. Kaech
Issue&Volume: 2024-12-12
Abstract: 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.
DOI: adj3020
Source: https://www.science.org/doi/10.1126/science.adj3020