Yang Yongbing, Wang Yanan, Wang Zhongcheng, Yan Huanyu, Gong Yi, Hu Yingchao, Jiang Yuying, Wen Shuang, Xu Feifei, Wang Bingwei, Humphries Fiachra, Chen Yun, Wang Xi, Yang Shuo
Department of Immunology, State Key Laboratory of Reproductive Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Gusu School, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, National Vaccine Innovation Platform, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
Department of Medical Laboratory, Affiliated Children's Hospital of Jiangnan University, Wuxi, China.
Nat Cell Biol. 2024 Mar;26(3):450-463. doi: 10.1038/s41556-024-01351-9. Epub 2024 Feb 7.
Memory CD8 T cells play a crucial role in infection and cancer and mount rapid responses to repeat antigen exposure. Although memory cell transcriptional programmes have been previously identified, the regulatory mechanisms that control the formation of CD8 T cells have not been resolved. Here we report ECSIT as an essential mediator of memory CD8 T cell differentiation. Ablation of ECSIT in T cells resulted in loss of fumarate synthesis and abrogated TCF-1 expression via demethylation of the TCF-1 promoter by the histone demethylase KDM5, thereby impairing memory CD8 T cell development in a cell-intrinsic manner. In addition, ECSIT expression correlated positively with stem-like memory progenitor exhausted CD8 T cells and the survival of patients with cancer. Our study demonstrates that ECSIT-mediated fumarate synthesis stimulates TCF-1 activity and memory CD8 T cell development during viral infection and tumorigenesis and highlights the utility of therapeutic fumarate analogues and PD-L1 inhibition for tumour immunotherapy.
记忆性CD8 T细胞在感染和癌症中发挥着关键作用，并能对重复的抗原暴露迅速做出反应。尽管记忆细胞转录程序此前已被确定，但控制CD8 T细胞形成的调控机制尚未得到解决。在此，我们报告ECSIT是记忆性CD8 T细胞分化的重要介质。T细胞中ECSIT的缺失导致富马酸盐合成丧失，并通过组蛋白去甲基化酶KDM5使TCF-1启动子去甲基化，从而废除TCF-1表达，进而以细胞内在方式损害记忆性CD8 T细胞的发育。此外，ECSIT表达与干细胞样记忆祖细胞耗竭的CD8 T细胞以及癌症患者的生存率呈正相关。我们的研究表明，ECSIT介导的富马酸盐合成在病毒感染和肿瘤发生过程中刺激TCF-1活性和记忆性CD8 T细胞发育，并强调了治疗性富马酸盐类似物和PD-L1抑制在肿瘤免疫治疗中的效用。
