Purine salvage pathway protects CD8+ T cells from metabolic stress

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Abstract
Metabolic stress from a high-fat diet (HFD) impairs antitumor immunity through persistent metabolic rewiring, but its effects and long-term impact on CD8+ T cell metabolism remain unknown. Here, we found that even temporary exposure to a HFD impaired antitumor immunity 10 weeks after reversion to a normal diet. This was due to lasting metabolome changes that included enrichment in phospholipids sensitive to peroxidation and depletion of antioxidants, affecting the survival and function of CD8+ T cells. Under oxidative stress, CD8+ T cells utilized the xanthine salvage pathway to produce guanosine triphosphate, enhancing the amount of tetrahydrobiopterin. Xanthine supplementation reduced lipid peroxidation in tumor-draining lymph nodes and improved antitumor immunity in mice previously on a HFD. Our data indicate that metabolic stress in CD8+ T cells persists long after restoration of a balanced diet, and manifests as vulnerability to ferroptosis, which could be mitigated by replenishing biopterins through the xanthine salvage pathway.
Funding Information
  • Japan Society for the Promotion of Science (24K10092)
  • Japan Society for the Promotion of Science (19K16881)
  • Japan Society for the Promotion of Science (22K15501)
  • Japan Society for the Promotion of Science (25H01031)
  • Mochida Memorial Foundation for Medical and Pharmaceutical Research
  • Astellas Foundation for Research on Metabolic Disorders
  • RIKEN
  • Takeda Medical Research Foundation
  • CCII fellowship
  • Exploratory Research for Advanced Technology (JPMJER2101)
  • Core Research for Evolutional Science and Technology (JPMJCR24T6)
  • Japan Agency for Medical Research and Development (JP25gm2010001)
  • Japan Agency for Medical Research and Development (25zf0127003)
  • Japan Agency for Medical Research and Development (25zf0127007)
  • Yanai Fund
  • Japan Science and Technology Agency (JPMJSP2110)

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