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

Cell Rep. 2021 Jun 15;35(11):109235. doi: 10.1016/j.celrep.2021.109235.

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.

Keywords: B16 melanoma; Gpx4; T(H)17 responses; TCR stimulation; Treg cells; ferroptosis; lipid peroxidation; mitochondria; tumor immune evasion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Ferroptosis*
  • Forkhead Transcription Factors / metabolism
  • Gene Deletion
  • Homeostasis
  • Immunity*
  • Interleukin-1beta / metabolism
  • Iron / metabolism
  • Lipid Peroxidation*
  • Lipid Peroxides / metabolism
  • Lymphocyte Activation / immunology*
  • Lymphoid Tissue / immunology
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • Neoplasms / immunology*
  • Phospholipid Hydroperoxide Glutathione Peroxidase / deficiency
  • Phospholipid Hydroperoxide Glutathione Peroxidase / metabolism*
  • Superoxides / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • Th17 Cells / immunology

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-1beta
  • Lipid Peroxides
  • Superoxides
  • Iron
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • glutathione peroxidase 4, mouse