Glutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function

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 respo...

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Published in:	Cell metabolism Vol. 31; no. 5; pp. 920 - 936.e7
Main Authors:	Kurniawan, Henry, Franchina, 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
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 05-05-2020
Subjects:	Animals autoimmunity cancer diet FoxP3 glutamate cysteine ligase glutathione Glutathione - metabolism Mice one carbon metabolism ROS Serine - metabolism T-Lymphocytes, Regulatory - metabolism Treg one carbon metabolism autoimmunity glutathione Treg ROS glutamate cysteine ligase cancer diet serine metabolism FoxP3
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Summary:	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. [Display omitted] •Ablation of Gclc in Tregs causes autoimmunity and increases anti-tumor responses•Gclc-derived GSH is needed for the suppressive function of Tregs in vitro and in vivo•GSH in Tregs regulates serine concentrations and metabolism. which impact mTOR and FoxP3•Serine- and glycine-deficient diet rescues mutant mice from lethal inflammation Regulatory T cells (Tregs) rely on oxidative metabolism, which triggers the generation of reactive oxygen species (ROS). Accumulating ROS are controlled by the antioxidant glutathione (GSH). Kurniawan et al. reveal an unexpected subset-specific role of GSH in serine metabolism and Treg function.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 DB, HK: study conception and manuscript writing. HK, DGF, LG, LB, LSB, MG, LS, CD, MPM, CB, GSD, SF, YN, JH, DDG, AE: data generation and analysis. RT, CBK: histology. RH, PW: RNA sequencing. OH: bioinformatics. HK, DGF, LSB, LS, CJ, JM, KH, YN, DB: metabolic analyses. TWM, ML, ISH, YC, MO, VV: expert comments and reagents. DB: study supervision. AUTHOR CONTRIBUTIONS lead author
ISSN:	1550-4131 1932-7420 1932-7420
DOI:	10.1016/j.cmet.2020.03.004