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Immunity. 2017 Apr 18;46(4):675-689. doi: 10.1016/j.immuni.2017.03.019.

Glutathione Primes T Cell Metabolism for Inflammation.

Author information

1
The Campbell Family Cancer Research Institute and University Health Network, Toronto, ON M5G 2C1, Canada; Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, ON M5G 2M9, Canada. Electronic address: tmak@uhnresearch.ca.
2
Department of Infection and Immunity, Experimental and Molecular Immunology, Luxembourg Institute of Health, Esch-sur-Alzette, L-4354, Luxembourg.
3
The Campbell Family Cancer Research Institute and University Health Network, Toronto, ON M5G 2C1, Canada.
4
Technische Universität Braunschweig, Braunschweig Integrated Center of Systems Biology, Braunschweig D-38106, Germany; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, L-4367, Luxembourg.
5
The Campbell Family Cancer Research Institute and University Health Network, Toronto, ON M5G 2C1, Canada; The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S3E1 Canada.
6
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia.
7
Department of Molecular Virology, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan.
8
Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, L-4367, Luxembourg.
9
Department of Environmental Health Sciences, Yale School of Public Health, CT 06520, New Haven, USA.
10
Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, Marburg, D-35032 Germany.
11
Department of Infection and Immunity, Allergy and Clinical Immunology, Luxembourg Institute of Health, Esch-sur-Alzette, L-4354, Luxembourg; Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, DK-5000, Denmark.
12
Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, DK-5000, Denmark.
13
Department of Molecular Medicine II, Medical Faculty, University of Düsseldorf, Düsseldorf, D-40225, Germany.
14
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
15
Technische Universität Braunschweig, Braunschweig Integrated Center of Systems Biology, Braunschweig D-38106, Germany; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, L-4367, Luxembourg; Computational Biology of Infection Research, Helmholtz Centre for Infection Research, Braunschweig, D-38124, Germany.
16
Department of Infection and Immunity, Experimental and Molecular Immunology, Luxembourg Institute of Health, Esch-sur-Alzette, L-4354, Luxembourg; Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, DK-5000, Denmark. Electronic address: dirk.brenner@lih.lu.

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.

KEYWORDS:

GSH; Gclc; Myc; NFAT; ROS; T cells; glutathione; glycolysis; mTOR; metabolic reprogramming; metabolism; reactive oxygen species

PMID:
28423341
DOI:
10.1016/j.immuni.2017.03.019
[Indexed for MEDLINE]
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