Transient high fat diet causes persistent susceptibility to ferroptosis in CD8 T cells [Ex_vivo_RNAseq]

Chronic metabolic stress impacts the immune cell function, increasing the incidence of autoimmune diseases and cancers. Whether past history of a high fat diet (HFD) leads to immune dysfunction is less understood. Moreover, whether factors other than persistent epigenetic changes would impact on the immune function remain unknown. We find that even a transient exposure to HFD causes persistent metabolome changes and long-term vulnerability of CD8 T cells to oxidative stress. The past HFD signature of CD8 T cells includes enrichment of lipid species highly susceptible to ferroptosis, and depletion of metabolites with anti-oxidant function. We find that xanthine, through the salvage purine pathway fuels the GTP, which is subsequently converted to tetrahydrobiopterin (BH4) and dihydrobiopterin (BH2). Xanthine-derived biopterins serve as ROS scavengers, rescuing CD8 T cells from activation-induced ferroptosis. Administration of xanthine or BH2 markedly reduces tumor growth in mice transiently fed HFD. Our data uncover that metabolic stress remains tattooed on membrane lipids, generating vulnerability to oxidative stress and ferroptosis, that can be mitigated by purine salvage pathway through the replenishment of guanines and biopterins pools.