Abstract：
The intestinal tract generates significant reactive oxygen species (ROS), but the role of T cell antioxidant mechanisms in maintaining intestinal homeostasis is poorly understood. We used T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), which impaired glutathione (GSH) production, crucially reducing IL-22 production by Th17 cells in the lamina propria, which is critical for gut protection. Under steady-state conditions, Gclc deficiency did not alter cytokine secretion; however, C. rodentium infection induced increased ROS and disrupted mitochondrial function and TFAM-driven mitochondrial gene expression, resulting in decreased cellular ATP. These changes impaired the PI3K/AKT/mTOR pathway, reducing phosphorylation of 4E-BP1 and consequently limiting IL-22 translation. The resultant low IL-22 levels led to poor bacterial clearance, severe intestinal damage, and high mortality. Our findings highlight a previously unrecognized, essential role of Th17 cell-intrinsic GSH in promoting mitochondrial function and cellular signaling for IL-22 protein synthesis, which is critical for intestinal integrity and defense against gastrointestinal infections.
摘要：
肠道产生显著的活性氧（ROS），但是对T细胞抗氧化机制在维持肠道稳态中的作用知之甚少。我们使用T细胞特异性消融谷氨酸半胱氨酸连接酶（Gclc）的催化亚基，这损害了谷胱甘肽（GSH）的生产，主要减少固有层中Th17细胞产生IL-22，这对肠道保护至关重要。在稳态条件下,Gclc缺乏不会改变细胞因子的分泌；然而，C.rodentium感染诱导增加的ROS和破坏的线粒体功能和TFAM驱动的线粒体基因表达，导致细胞ATP减少。这些改变损害了PI3K/AKT/mTOR通路,减少4E-BP1的磷酸化，从而限制IL-22的翻译。由此产生的低IL-22水平导致细菌清除不良，严重的肠道损伤，和高死亡率。我们的发现强调了一个以前无法识别的，Th17细胞内在GSH在促进线粒体功能和细胞信号转导中的重要作用IL-22蛋白合成，这对于肠道完整性和防御胃肠道感染至关重要。
