Glutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function.
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Authors
Kurniawan, HenryFranchina, Davide G
Guerra, Luana
Bonetti, Lynn
-Baguet, Leticia Soriano
Grusdat, Melanie
Schlicker, Lisa
Hunewald, Oliver
Dostert, Catherine
Merz, Myriam P
Binsfeld, Carole
Duncan, Gordon S
Farinelle, Sophie
Nonnenmacher, Yannic
Haight, Jillian
Das Gupta, Dennis
Ewen, Anouk
Taskesen, Rabia
Halder, Rashi
Chen, Ying
Jäger, Christian
Ollert, Markus
Wilmes, Paul
Vasiliou, Vasilis
Harris, Isaac S
Knobbe-Thomsen, Christiane B
Turner, Jonathan D
Mak, Tak W
Lohoff, Michael
Meiser, Johannes
Hiller, Karsten
Brenner, Dirk
Issue Date
2020-03-25
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Show full item recordAbstract
Regulatory T cells (Tregs) maintain immune homeostasis and prevent autoimmunity. Serine stimulates glutathione (GSH) synthesis and feeds into the one-carbon metabolic network (1CMet) essential for effector T cell (Teff) responses. However, serine's functions, linkage to GSH, and role in stress responses in Tregs are unknown. Here, we show, using mice with Treg-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that GSH loss in Tregs alters serine import and synthesis and that the integrity of this feedback loop is critical for Treg suppressive capacity. Although Gclc ablation does not impair Treg differentiation, mutant mice exhibit severe autoimmunity and enhanced anti-tumor responses. Gclc-deficient Tregs show increased serine metabolism, mTOR activation, and proliferation but downregulated FoxP3. Limitation of cellular serine in vitro and in vivo restores FoxP3 expression and suppressive capacity of Gclc-deficient Tregs. Our work reveals an unexpected role for GSH in restricting serine availability to preserve Treg functionality.Citation
Cell Metab. 2020;31(5):920-936.e7. doi:10.1016/j.cmet.2020.03.004.Affiliation
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.Publisher
Elsevier (Cell Press)Journal
Cell metabolismPubMed ID
32213345Type
ArticleLanguage
enEISSN
1932-7420ae974a485f413a2113503eed53cd6c53
10.1016/j.cmet.2020.03.004
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