Glutathione Primes T Cell Metabolism for Inflammation.
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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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Mice, Inbred C57BL
Encephalomyelitis, Autoimmune, Experimental
Reactive Oxygen Species
Proto-Oncogene Proteins c-myc
NFATC Transcription Factors
TOR Serine-Threonine Kinases
Target Evaluation and Molecular Therapeutics
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Immunity, 2017, 46 (4), pp. 675 - 689