AI Summary
Iron metabolism in group 3 innate lymphoid cells (ILC3s) controls cell proliferation, host protection against infection, and mitochondrial respiration. The aryl hydrocarbon receptor (Ahr) regulates the expression of the transferrin receptor CD71, which mediates iron uptake. Ahr directly inhibits CD71 transcription by binding to its promoter. Iron overload partly restores ILC3 function in Ahr-deficient mice. This study highlights the role of the Ahr-CD71-iron axis in the regulation of ILC3 maintenance and function.
Iron metabolism is pivotal for cell fitness in the mammalian host; however, its role in group 3 innate lymphoid cells (ILC3s) is unknown. Here we show that transferrin receptor CD71 (encoded by Tfrc)-mediated iron metabolism cell-intrinsically controls ILC3 proliferation and host protection against Citrobacter rodentium infection and metabolically affects mitochondrial respiration by switching of oxidative phosphorylation toward glycolysis. Iron deprivation or Tfrc ablation in ILC3s reduces the expression and/or activity of the aryl hydrocarbon receptor (Ahr), a key ILC3 regulator. Genetic ablation or activation of Ahr in ILC3s leads to CD71 upregulation or downregulation, respectively, suggesting Ahr-mediated suppression of CD71. Mechanistically, Ahr directly binds to the Tfrc promoter to inhibit transcription. Iron overload partially restores the defective ILC3 compartment in the small intestine of Ahr-deficient mice, consistent with the compensatory upregulation of CD71. These data collectively demonstrate an under-appreciated role of the Ahr-CD71–iron axis in the regulation of ILC3 maintenance and function.
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