The glutathione peroxidase Gpx4 prevents lipid peroxidation and ferroptosis to sustain Treg cell activation and suppression of antitumor immunity
| Autor: | Shaogang Sun, Kai Yang, Rong Qi, Siyuan Zhang, Chengxian Xu, Jie Zhang, Travis S. Johnson |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Lipid Peroxides QH301-705.5 Lymphoid Tissue Iron Interleukin-1beta chemical and pharmacologic phenomena Mitochondrion GPX4 Lymphocyte Activation T-Lymphocytes Regulatory General Biochemistry Genetics and Molecular Biology Immune tolerance Lipid peroxidation 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Superoxides Cell Line Tumor Neoplasms Animals Ferroptosis Homeostasis Biology (General) chemistry.chemical_classification Glutathione peroxidase T-cell receptor Immunity CD28 hemic and immune systems Forkhead Transcription Factors Phospholipid Hydroperoxide Glutathione Peroxidase Cell biology Mitochondria Mice Inbred C57BL 030104 developmental biology chemistry Th17 Cells Lipid Peroxidation Gpx4 TCR stimulation Treg cells 030217 neurology & neurosurgery Gene Deletion |
| Zdroj: | Cell Reports, Vol 35, Iss 11, Pp 109235-(2021) |
| ISSN: | 2211-1247 |
| Popis: | Summary: 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. |
| Databáze: | OpenAIRE |
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