Nutrition impact on ILC3 maintenance and function centers on a cell-intrinsic CD71-iron axis

Area of Science:

• Immunology
• Cell Biology
• Metabolism

Background:

• Iron metabolism is essential for mammalian cell function.
• The role of iron in group 3 innate lymphoid cells (ILC3s) was previously unknown.
• Group 3 innate lymphoid cells (ILC3s) are critical for host defense and tissue homeostasis.

Purpose of the Study:

• To investigate the role of iron metabolism in ILC3 proliferation and function.
• To elucidate the molecular mechanisms linking iron metabolism to ILC3 regulation.
• To determine the interplay between iron metabolism, the aryl hydrocarbon receptor (Ahr), and ILC3s.

Main Methods:

• Utilized mouse models with genetic ablation or manipulation of transferrin receptor CD71 (Tfrc) and aryl hydrocarbon receptor (Ahr) in ILC3s.
• Assessed ILC3 proliferation, host protection against Citrobacter rodentium infection, and mitochondrial respiration.
• Analyzed gene expression, protein activity, and direct promoter binding of Ahr to the Tfrc gene.

Main Results:

• CD71-mediated iron metabolism intrinsically controls ILC3 proliferation and host protection.
• Iron deprivation or Tfrc ablation in ILC3s reduces Ahr expression/activity.
• Ahr directly inhibits Tfrc transcription, and iron overload can rescue ILC3 defects in Ahr-deficient mice.

Conclusions:

• The Ahr-CD71-iron axis is a critical regulator of ILC3 maintenance and function.
• This pathway influences ILC3 metabolic reprogramming from oxidative phosphorylation to glycolysis.
• Understanding this axis offers insights into immune cell fitness and host defense mechanisms.