Glutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function

Henry Kurniawan, Davide G. Franchina, Luana Guerra, Lynn Bonetti, Leticia Soriano Baguet, Melanie Grusdat, Lisa Schlicker, Oliver Hunewald, Catherine Dostert, Myriam P. Merz, Carole Binsfeld, Gordon S. Duncan, Sophie Farinelle, Yannic Nonnenmacher, Jillian Haight, Dennis Das Gupta, Anouk Ewen, Rabia Taskesen, Rashi Halder, Ying ChenChristian Jäger, Markus Ollert, Paul Wilmes, Vasilis Vasiliou, Isaac S. Harris, Christiane B. Knobbe-Thomsen, Jonathan D. Turner, Tak W. Mak, Michael Lohoff, Johannes Meiser, Karsten Hiller, Dirk Brenner*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

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.

Original languageEnglish
JournalCell Metabolism
Volume31
Issue number5
Pages (from-to)920-936.e7
ISSN1550-4131
DOIs
Publication statusPublished - 5. May 2020

Keywords

  • autoimmunity
  • cancer
  • diet
  • FoxP3
  • glutamate cysteine ligase
  • glutathione
  • one carbon metabolism
  • ROS
  • serine metabolism
  • Treg

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