Dietary Iron Overload Rewires Regulatory T Cells into IL-17—Mediated Proinflammatory Effectors Aggravating Yersinia enterocolitica Infection 2259908

Abstract Introduction Iron is indispensable for host physiology but, when in excess, fuels inflammatory and infectious diseases. The mechanisms by which nutritional iron overload perturbs adaptive immunity remain unclear. Here, we show that a high-iron diet (HID) profoundly reprograms FoxP3+ regulatory T (Treg) cells into IL-17—producing proinflammatory effectors that exacerbate Yersinia enterocolitica infection. Methods Mice were on a high iron diet for 4 weeks to generate iron overload followed by infection with YE. Control mice were fed control diet with normal iron. Changes in immune parametrs were evaluated by microscopy and flow cytometry analysis. Role of specific cell types were evaluated by adoptive transfer assays. Results HID-fed mice displayed a striking loss of reparative ST2+ Tregs and expansion of IL-17+ FoxP3+ Tregs with Th17-like transcriptional and metabolic signatures. Iron-conditioned Tregs exhibited enhanced mTORC1 activation, glycolytic flux, and RORγt expression, driving secretion of IL-17A and CXCL1 that promoted excessive neutrophil infiltration and mucosal damage. Neutralization of IL-17, inhibition of glycolysis (2-DG), or iron chelation (deferoxamine) restored ST2+ Tregs, reduced neutrophilia, and improved survival. Mechanistically, mTOR inhibition with rapamycin prevented iron-induced metabolic reprogramming, confirming an iron—mTOR—glycolysis axis that destabilizes Treg identity. Adoptive transfer experiments demonstrated that IL-17+ Tregs are pathogenic, whereas canonical ST2+ Tregs confer protection. Conclusion These findings uncover a previously unrecognized nutritional-immune checkpoint in which excess dietary iron converts reparative Tregs into proinflammatory effectors, amplifying neutrophil-driven immunopathology. Targeting this metabolic axis offers therapeutic promise for iron-associated inflammatory and infectious disorders. Funding Source RO1AI162670 Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)