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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE276598 | GEO | 2026/03/06

REPOSITORIES: GEO

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Project description:The ability of Leishmania to survive in their insect or mammalian host is dependent upon an ability to sense and adapt to changes in the microenvironment. However, little is known about the molecular mechanisms underlying the parasite response to environmental changes, such as nutrient availability. To elucidate nutrient stress response pathways in Leishmania donovani, we have used purine starvation as the paradigm. The salvage of purines from the host milieu is obligatory for parasite replication; nevertheless, purine-starved parasites can persist in culture without supplementary purine for over 3 months, indicating that the response to purine starvation is robust and engenders parasite survival under conditions of extreme scarcity. To understand metabolic reprogramming during purine starvation we have employed global approaches. Whole proteome comparisons between purine-starved and purine-replete parasites over a 6-48 h span have revealed a temporal and coordinated response to purine starvation. Purine transporters and enzymes involved in acquisition at the cell surface are upregulated within a few hours of purine removal from the media, while other key purine salvage components are upregulated later in the time-course and more modestly.Â After 48 h, the proteome of purine-starved parasites is extensively remodeled and adaptations to purine stress appear tailored to deal with both purine deprivation and general stress. To probe the molecular mechanisms affecting proteome remodeling in response to purine starvation, comparative RNA-seq analyses, qRT-PCR, and luciferase reporter assays were performed on purine-starved versus purine-replete parasites.Â While the regulation of a minority of proteins tracked with changes at the mRNA level, for many regulated proteins it appears that proteome remodeling during purine stress occurs primarily via translational and post-translational mechanisms. One mRNA sample from each of Purine-Starved and Purine-Replete cells were analyzed using SL RNA-Seq methodology

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

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