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Glutathione Primes T Cell Metabolism for Inflammation

Mak, TW;Grusdat, M;Duncan, GS;Dostert, C;Nonnenmacher, Y;Cox, M;Binsfeld, C;Hao, Z;Brstle, A;Itsumi, M;Jger, C;Chen, Y;Pinkenburg, O;Camara, B;Ollert, M;Bindslev-Jensen, C;Vasiliou, V;Gorrini, C;Lang, PA;Lohoff, M;Harris, IS;Hiller, K;Brenner, D;

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.