Iron Regulates CD4 T Cell Quiescence by Controlling TGF-β Production

Transforming growth factor-β (TGF-β) regulates CD4 T cell quiescence, activation, and regulatory T cell differentiation, but its role in T cell iron metabolism is poorly defined. Here, we investigated whether TGF-β regulates iron homeostasis and how iron overload alters TGF-β responsiveness. During T cell activation, TGF-β enhanced survival but markedly reduced proliferation. These effects were accompanied by decreased CD71 expression and cytosolic iron availability, as well as increased mitochondrial iron accumulation. Genetic deletion of TGFβR1 reversed these changes, demonstrating that TGF-β regulates CD4 T cell iron homeostasis through TGFβR1-dependent signaling. Iron-overloaded CD4 T cells lacking the heme exporter FLVCR1 exhibit hypersensitivity to TGF-β, increased TGF-β secretion, and sustained TGFβR1 expression upon activation. Pharmacologic inhibition of TGFβR1restored proliferation, CD71 expression, and iron levels in FLVCR1-deficient cells. Although TGF-β selectively induced total and mitochondrial ROS levels in FLVCR1-deficient cells, antioxidant treatment or Nox2 inhibition did not rescue this phenotype, suggesting that ROS is associated with, but not sufficient to explain, TGF-β hypersensitivity. Acute FeSO ₄ -induced iron overload partially recapitulated the phenotype of FLVCR1-deficient cells, although TGFβR1 expression and TGF-β production differed. Finally, regulatory T cells generated in vitro in the presence of TGF-β displayed reduced iron acquisition, and excess iron impaired FoxP3 induction. Together, this work identifies TGF-β as a context-dependent regulator of CD4 T cell iron homeostasis.