Glutathione primes t cell metabolism for inflammation
Open accessAbstract
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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- Authors
- Mak, T. W., Grusdat, M., Duncan, G. S., 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, P. A., Lohoff, M., Harris, I. S., Hiller, K., & Brenner, D.
- Affiliations
- University Health Network (CA)
- Luxembourg Institute of Health (LU)
- University of Luxembourg (LU)
- Australian National University (AU)
- Tokyo Medical and Dental University (JP)
- Yale University (US)
- Philipps University of Marburg (DE)
- University of Southern Denmark (DK)
- Heinrich Heine University Düsseldorf (DE)
- Harvard University (US)
- Corresponding author
- Mak, Tak W.
- Brenner, Dirk
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 46
- Issue
- 4
- Pages
- 675-689
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2607349616
- Cited by
- 511
- References
- 55
- Citations by year
- 2026: 37 · 2025: 65 · 2024: 66 · 2023: 60 · 2022: 70 · 2021: 72 · 2020: 60 · 2019: 38 · 2018: 34 · 2017: 8 · 2014: 1
- FWCI
- 15.63
- Type
- journal article
- Language
- en
- Update notices
- erratum (2017-06-20)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion, other-oa)
- ANU Open Research (Australian National University) (submittedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion)
- Funders
- ATTRACT program
- CORE (C15/BM/10355103)
- National Research Fund Luxembourg
- NIH NIAAA (5R24AA022057-05)
- German Research Council
- DFG (SFB974, LA-2558-5/1)
- Deutsches Zentrum für Infektionsforschung
- University Hospital Giessen Marburg
- National Multiple Sclerosis Society (RG 5035-A-2)
- Canadian Institutes of Health Research (143268, MOP-123276)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Keywords
- glutathione, T cell metabolism, gamma-glutamylcysteine synthetase, GCLC, reactive oxygen species, oxidative stress, mTOR signaling, NFAT, c-Myc, metabolic reprogramming, glycolysis, glutaminolysis, T cell activation, inflammation, autoimmune disease, antiviral immunity, conditional knockout
- MeSH terms
- Animals, Encephalomyelitis, Autoimmune, Experimental, Energy Metabolism, Glutamate-Cysteine Ligase, Glutamine, Glutathione, Glycolysis, Inflammation, Mice, Inbred C57BL, T-Lymphocytes, Immunoblotting, Signal Transduction, Proto-Oncogene Proteins c-myc, Reactive Oxygen Species, Mice, Knockout, NFATC Transcription Factors, TOR Serine-Threonine Kinases
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