[PDF][PDF] Glutathione primes T cell metabolism for inflammation

TW Mak, M Grusdat, GS Duncan, C Dostert… - Immunity, 2017 - cell.com
TW Mak, M Grusdat, GS Duncan, C Dostert, Y Nonnenmacher, M Cox, C Binsfeld, Z Hao…
Immunity, 2017cell.com
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 …
Summary
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.
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