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

• DOI: 10.1016/j.celrep.2021.109235
• Publication Date: 2021-06-15T14:46:00Z
• Authors: Chengxian Xu; Shaogang Sun; Travis Johnson; Rong Qi; Siyuan Zhang; Jie Zhang; Kai Yang
• Keywords: 0301 basic medicine; Lipid Peroxides; QH301-705.5; Lymphoid Tissue; Iron; Interleukin-1beta; 610; Lymphocyte Activation; T-Lymphocytes, Regulatory; 03 medical and health sciences; Superoxides; Cell Line, Tumor; Neoplasms; Animals; Ferroptosis; Homeostasis; Biology (General); Immunity; lipid peroxidation; Forkhead Transcription Factors; Phospholipid Hydroperoxide Glutathione Peroxidase; ferroptosis; Mitochondria; 3. Good health; mitochondria; Mice, Inbred C57BL; B16 melanoma; Th17 Cells; Lipid Peroxidation; Gpx4; TCR stimulation; Treg cells; Gene Deletion

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.