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Article: Glutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function

TitleGlutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function
Authors
KeywordsTreg
serine metabolism
autoimmunity
ROS
FoxP3
glutamate cysteine ligase
one carbon metabolism
glutathione
cancer
diet
Issue Date2020
Citation
Cell Metabolism, 2020, v. 31, n. 5, p. 920-936.e7 How to Cite?
Abstract© 2020 Elsevier Inc. 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. 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.
Persistent Identifierhttp://hdl.handle.net/10722/292155
ISSN
2023 Impact Factor: 27.7
2023 SCImago Journal Rankings: 11.406
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorKurniawan, Henry-
dc.contributor.authorFranchina, Davide G.-
dc.contributor.authorGuerra, Luana-
dc.contributor.authorBonetti, Lynn-
dc.contributor.authorBaguet, Leticia Soriano-
dc.contributor.authorGrusdat, Melanie-
dc.contributor.authorSchlicker, Lisa-
dc.contributor.authorHunewald, Oliver-
dc.contributor.authorDostert, Catherine-
dc.contributor.authorMerz, Myriam P.-
dc.contributor.authorBinsfeld, Carole-
dc.contributor.authorDuncan, Gordon S.-
dc.contributor.authorFarinelle, Sophie-
dc.contributor.authorNonnenmacher, Yannic-
dc.contributor.authorHaight, Jillian-
dc.contributor.authorDas Gupta, Dennis-
dc.contributor.authorEwen, Anouk-
dc.contributor.authorTaskesen, Rabia-
dc.contributor.authorHalder, Rashi-
dc.contributor.authorChen, Ying-
dc.contributor.authorJäger, Christian-
dc.contributor.authorOllert, Markus-
dc.contributor.authorWilmes, Paul-
dc.contributor.authorVasiliou, Vasilis-
dc.contributor.authorHarris, Isaac S.-
dc.contributor.authorKnobbe-Thomsen, Christiane B.-
dc.contributor.authorTurner, Jonathan D.-
dc.contributor.authorMak, Tak W.-
dc.contributor.authorLohoff, Michael-
dc.contributor.authorMeiser, Johannes-
dc.contributor.authorHiller, Karsten-
dc.contributor.authorBrenner, Dirk-
dc.date.accessioned2020-11-17T14:55:53Z-
dc.date.available2020-11-17T14:55:53Z-
dc.date.issued2020-
dc.identifier.citationCell Metabolism, 2020, v. 31, n. 5, p. 920-936.e7-
dc.identifier.issn1550-4131-
dc.identifier.urihttp://hdl.handle.net/10722/292155-
dc.description.abstract© 2020 Elsevier Inc. 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. 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.-
dc.languageeng-
dc.relation.ispartofCell Metabolism-
dc.subjectTreg-
dc.subjectserine metabolism-
dc.subjectautoimmunity-
dc.subjectROS-
dc.subjectFoxP3-
dc.subjectglutamate cysteine ligase-
dc.subjectone carbon metabolism-
dc.subjectglutathione-
dc.subjectcancer-
dc.subjectdiet-
dc.titleGlutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1016/j.cmet.2020.03.004-
dc.identifier.pmid32213345-
dc.identifier.pmcidPMC7265172-
dc.identifier.scopuseid_2-s2.0-85083873378-
dc.identifier.volume31-
dc.identifier.issue5-
dc.identifier.spage920-
dc.identifier.epage936.e7-
dc.identifier.eissn1932-7420-
dc.identifier.isiWOS:000544625500009-
dc.identifier.issnl1550-4131-

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