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bioRxiv · 10.64898/2026.06.18.733147

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

Siglin, A. L.·Han, Z.·Nkansah, A.·Chen, W.·Chang, C.-H.
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Abstract

Transforming growth factor-{beta} (TGF-{beta}) 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-{beta} regulates iron homeostasis and how iron overload alters TGF-{beta} responsiveness. During T cell activation, TGF-{beta} 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 TGF{beta}R1 reversed these changes, demonstrating that TGF-{beta} regulates CD4 T cell iron homeostasis through TGF{beta}R1-dependent signaling. Iron-overloaded CD4 T cells lacking the heme exporter FLVCR1 exhibit hypersensitivity to TGF-{beta}, increased TGF-{beta} secretion, and sustained TGF{beta}R1 expression upon activation. Pharmacologic inhibition of TGF{beta}R1restored proliferation, CD71 expression, and iron levels in FLVCR1-deficient cells. Although TGF-{beta} 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-{beta} hypersensitivity. Acute FeSO4-induced iron overload partially recapitulated the phenotype of FLVCR1-deficient cells, although TGF{beta}R1 expression and TGF-{beta} production differed. Finally, regulatory T cells generated in vitro in the presence of TGF-{beta} displayed reduced iron acquisition, and excess iron impaired FoxP3 induction. Together, this work identifies TGF-{beta} as a context-dependent regulator of CD4 T cell iron homeostasis.

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Siglin, A. L., Han, Z., Nkansah, A., Chen, W., Chang, C.-H.. 2026-06-23. Iron Regulates CD4 T Cell Quiescence by Controlling TGF-β Production. https://doi.org/10.64898/2026.06.18.733147

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