The glutathione peroxidase Gpx4 prevents lipid peroxidation and ferroptosis to sustain Treg cell activation and suppression of antitumor immunity

Chengxian Xu, Shaogang Sun, Travis Johnson, Rong Qi, Siyuan Zhang, Jie Zhang, Kai Yang

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

T regulatory (Treg) cells are crucial to maintain immune tolerance and repress antitumor immunity, but the mechanisms governing their cellular redox homeostasis remain elusive. We report that glutathione peroxidase 4 (Gpx4) prevents Treg cells from lipid peroxidation and ferroptosis in regulating immune homeostasis and antitumor immunity. Treg-specific deletion of Gpx4 impairs immune homeostasis without substantially affecting survival of Treg cells at steady state. Loss of Gpx4 results in excessive accumulation of lipid peroxides and ferroptosis of Treg cells upon T cell receptor (TCR)/CD28 co-stimulation. Neutralization of lipid peroxides and blockade of iron availability rescue ferroptosis of Gpx4-deficient Treg cells. Moreover, Gpx4-deficient Treg cells elevate generation of mitochondrial superoxide and production of interleukin-1β (IL-1β) that facilitates T helper 17 (TH17) responses. Furthermore, Treg-specific ablation of Gpx4 represses tumor growth and concomitantly potentiates antitumor immunity. Our studies establish a crucial role for Gpx4 in protecting activated Treg cells from lipid peroxidation and ferroptosis and offer a potential therapeutic strategy to improve cancer treatment.

Original languageEnglish (US)
Article number109235
JournalCell Reports
Volume35
Issue number11
DOIs
StatePublished - Jun 15 2021
Externally publishedYes

Keywords

  • B16 melanoma
  • ferroptosis
  • Gpx4
  • lipid peroxidation
  • mitochondria
  • T17 responses
  • TCR stimulation
  • Treg cells
  • tumor immune evasion

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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