Iron and Ferritin Modulate MHC Class I Expression and NK Cell Recognition

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Pathogen virulence is linked to iron acquisition from hosts.
• Iron is crucial for both innate and acquired immune responses.
• Intracellular iron levels may dictate host-pathogen-immune system dynamics.

Purpose of the Study:

• To investigate how iron concentration and ferritin heavy chain (FTH) abundance affect Major Histocompatibility Complex (MHC) molecule expression.
• To determine the impact of iron and FTH on Natural Killer (NK) cell cytotoxicity susceptibility.

Main Methods:

• Downregulation of FTH using shRNA transfection and iron chelation.
• Analysis of MHC surface expression in primary cancer cells and macrophages.
• Examination of NCOA4 null mouse embryonic fibroblasts (MEFs) with impaired ferritinophagy.
• Assessment of IFN-γ receptor signaling, STAT1 phosphorylation, and nuclear translocation.
• Evaluation of NK cell recognition and target cell susceptibility.

Main Results:

• FTH downregulation reduced MHC surface expression in cancer cells and macrophages.
• MEFs with impaired ferritinophagy overexpressed MHC class I.
• Low iron, not FTH, inhibited IFN-γ-induced MHC class I upregulation by blocking STAT1.
• Iron depletion and FTH downregulation enhanced NK cell-mediated lysis of cancer cells and macrophages.

Conclusions:

• Iron and FTH levels significantly influence MHC class I expression.
• Reduced iron and FTH increase susceptibility to NK cell-mediated immune responses.
• Modulating iron homeostasis could be a strategy to enhance anti-tumor immunity.