The Campbell Family Cancer Research Institute and University Health Network, Toronto, ON M5G 2C1, Canada; Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, ON M5G 2M9, Canada.
Department of Infection and Immunity, Experimental and Molecular Immunology, Luxembourg Institute of Health, Esch-sur-Alzette, L-4354, Luxembourg.
Immunity. 2017 Apr 18;46(4):675-689. doi: 10.1016/j.immuni.2017.03.019.
Activated T cells produce reactive oxygen species (ROS), which trigger the antioxidative glutathione (GSH) response necessary to buffer rising ROS and prevent cellular damage. We report that GSH is essential for T cell effector functions through its regulation of metabolic activity. Conditional gene targeting of the catalytic subunit of glutamate cysteine ligase (Gclc) blocked GSH production specifically in murine T cells. Gclc-deficient T cells initially underwent normal activation but could not meet their increased energy and biosynthetic requirements. GSH deficiency compromised the activation of mammalian target of rapamycin-1 (mTOR) and expression of NFAT and Myc transcription factors, abrogating the energy utilization and Myc-dependent metabolic reprogramming that allows activated T cells to switch to glycolysis and glutaminolysis. In vivo, T-cell-specific ablation of murine Gclc prevented autoimmune disease but blocked antiviral defense. The antioxidative GSH pathway thus plays an unexpected role in metabolic integration and reprogramming during inflammatory T cell responses.
活化的 T 细胞会产生活性氧（ROS），ROS 会触发抗氧化谷胱甘肽（GSH）反应，这是缓冲不断上升的 ROS 并防止细胞损伤所必需的。我们报告称，GSH 通过调节代谢活性对 T 细胞效应功能至关重要。通过条件性基因靶向敲除谷氨酸半胱氨酸连接酶（Gclc）的催化亚基，可以特异性阻断小鼠 T 细胞中的 GSH 产生。Gclc 缺陷型 T 细胞最初经历了正常的激活，但无法满足其增加的能量和生物合成需求。GSH 缺乏会损害雷帕霉素靶蛋白-1（mTOR）的激活和 NFAT 和 Myc 转录因子的表达，从而破坏允许激活的 T 细胞切换到糖酵解和谷氨酰胺分解的能量利用和 Myc 依赖性代谢重编程。在体内，特异性敲除小鼠 Gclc 会阻止自身免疫性疾病，但会阻断抗病毒防御。因此，抗氧化 GSH 途径在炎症性 T 细胞反应中的代谢整合和重编程中发挥了意想不到的作用。
