Glutathione Primes T Cell Metabolism for Inflammation.
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ICR Authors
Authors
Mak, TW
Grusdat, M
Duncan, GS
Dostert, C
Nonnenmacher, Y
Cox, M
Binsfeld, C
Hao, Z
Brüstle, A
Itsumi, M
Jäger, 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
Grusdat, M
Duncan, GS
Dostert, C
Nonnenmacher, Y
Cox, M
Binsfeld, C
Hao, Z
Brüstle, A
Itsumi, M
Jäger, 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
Document Type
Journal Article
Date
2017-04-18
Date Accepted
2017-03-29
Abstract
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.
Citation
Immunity, 2017, 46 (4), pp. 675 - 689
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Publisher
CELL PRESS
ISSN
1074-7613
eISSN
1097-4180
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Research Team
Target Evaluation and Molecular Therapeutics