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 language | English (US) |
---|---|
Article number | 109235 |
Journal | Cell Reports |
Volume | 35 |
Issue number | 11 |
DOIs | |
State | Published - Jun 15 2021 |
Externally published | Yes |
Keywords
- B16 melanoma
- Gpx4
- T17 responses
- TCR stimulation
- Treg cells
- ferroptosis
- lipid peroxidation
- mitochondria
- tumor immune evasion
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology