Glutathione Primes T Cell Metabolism for Inflammation

Tak W Mak¹, Melanie Grusdat², Gordon S Duncan³, Catherine Dostert², Yannic Nonnenmacher⁴, Maureen Cox³, Carole Binsfeld², Zhenyue Hao⁵, Anne Brüstle⁶, Momoe Itsumi⁷, Christian Jäger⁸, Ying Chen⁹, Olaf Pinkenburg¹⁰, Bärbel Camara¹⁰, Markus Ollert¹¹, Carsten Bindslev-Jensen¹², Vasilis Vasiliou⁹, Chiara Gorrini³, Philipp A Lang¹³, Michael Lohoff¹⁰, Isaac S Harris¹⁴, Karsten Hiller¹⁵, Dirk Brenner¹⁶

Affiliations

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.

PMID: 28423341
DOI: 10.1016/j.immuni.2017.03.019

Free article

Glutathione Primes T Cell Metabolism for Inflammation

Tak W Mak et al. Immunity. 2017.

Free article

. 2017 Apr 18;46(4):675-689.

doi: 10.1016/j.immuni.2017.03.019.

Authors

Affiliations

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.

PMID: 28423341
DOI: 10.1016/j.immuni.2017.03.019

Erratum in

Glutathione Primes T Cell Metabolism for Inflammation.
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. Mak TW, et al. Immunity. 2017 Jun 20;46(6):1089-1090. doi: 10.1016/j.immuni.2017.06.009. Immunity. 2017. PMID: 28636957 No abstract available.

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.

PubMed Disclaimer

Comment in

Caught in the cROSsfire: GSH Controls T Cell Metabolic Reprogramming.
Klein Geltink RI, O'Sullivan D, Pearce EL. Klein Geltink RI, et al. Immunity. 2017 Apr 18;46(4):525-527. doi: 10.1016/j.immuni.2017.03.022. Immunity. 2017. PMID: 28423332 Free PMC article.

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
- Elsevier Science
- Ovid Technologies, Inc.
Other Literature Sources
Molecular Biology Databases
- Mouse Genome Informatics (MGI)
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Glutathione Primes T Cell Metabolism for Inflammation

Affiliations

Glutathione Primes T Cell Metabolism for Inflammation

Authors

Affiliations

Erratum in

Abstract

Comment in

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases

Miscellaneous