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Glutathione Primes T Cell Metabolism for Inflammation.

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Date
2017-04
ICR Author
Gorrini, Chiara
Author
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
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Type
Journal Article
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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.
URI
https://repository.icr.ac.uk/handle/internal/4099
DOI
https://doi.org/10.1016/j.immuni.2017.03.019
Collections
  • Cancer Therapeutics
Subject
T-Lymphocytes
Animals
Mice, Inbred C57BL
Mice, Knockout
Encephalomyelitis, Autoimmune, Experimental
Inflammation
Reactive Oxygen Species
Glutamate-Cysteine Ligase
Glutamine
Glutathione
Proto-Oncogene Proteins c-myc
Immunoblotting
Signal Transduction
Energy Metabolism
Glycolysis
NFATC Transcription Factors
TOR Serine-Threonine Kinases
Research team
Target Evaluation and Molecular Therapeutics
Language
eng
Date accepted
2017-03-29
License start date
2017-04
Citation
Immunity, 2017, 46 (4), pp. 675 - 689

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