Follicular T helper (TFH) cells are a specialized subset of CD4+ T cells that essentially support germinal center (GC) responses where high-affinity and long-lived humoral immunity is generated. The regulation of TFH cell survival is not well understood. We discovered that the homeostasis of TFH cells in mice with protein immunization is essentially regulated by ferroptosis, a newly identified form of non-apoptotic programmed death pathway characterized by excessive lipid peroxidation. Mouse TFH cells show features of ferroptosis including higher lipid peroxidation and transferrin expression than those of non-TFH cells. Glutathione peroxidase 4 (GPX4), the major lipid peroxidation scavenger to prevent ferroptosis, is required for TFH cells to survive. Genetically depleting Gpx4 in CD4+ T cells predominantly abrogated TFH cell function, GC responses and the production of protective antibodies in mice with protein immunization or SARS-CoV-2 vaccination. Reversely, pharmaceutical inhibition of ferroptosis promoted antibody responses in immunized mice. Our findings reveal the central role of the GPX4–ferroptosis axis in regulating TFH homeostasis, which can be targeted to enhance TFH cell function in infection and following vaccination.
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