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

Front Immunol. 2019 Feb 26:10:224. doi: 10.3389/fimmu.2019.00224. eCollection 2019.

Abstract

The ability of pathogens to sequester iron from their host cells and proteins affects their virulence. Moreover, iron is required for various innate host defense mechanisms as well as for acquired immune responses. Therefore, intracellular iron concentration may influence the interplay between pathogens and immune system. Here, we investigated whether changes in iron concentrations and intracellular ferritin heavy chain (FTH) abundance may modulate the expression of Major Histocompatibility Complex molecules (MHC), and susceptibility to Natural Killer (NK) cell cytotoxicity. FTH downregulation, either by shRNA transfection or iron chelation, led to MHC surface reduction in primary cancer cells and macrophages. On the contrary, mouse embryonic fibroblasts (MEFs) from NCOA4 null mice accumulated FTH for ferritinophagy impairment and displayed MHC class I cell surface overexpression. Low iron concentration, but not FTH, interfered with IFN-γ receptor signaling, preventing the increase of MHC-class I molecules on the membrane by obstructing STAT1 phosphorylation and nuclear translocation. Finally, iron depletion and FTH downregulation increased the target susceptibility of both primary cancer cells and macrophages to NK cell recognition. In conclusion, the reduction of iron and FTH may influence the expression of MHC class I molecules leading to NK cells activation.

Keywords: HLA; IFNγ; MHC-I; NK cells; STAT1; iron.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoferritins / genetics
  • Apoferritins / metabolism*
  • Cell Line, Tumor
  • Cells, Cultured
  • Cytotoxicity, Immunologic / genetics
  • Cytotoxicity, Immunologic / immunology*
  • Deferoxamine / pharmacology
  • Embryo, Mammalian / cytology
  • Fibroblasts / cytology
  • Fibroblasts / immunology
  • Fibroblasts / metabolism
  • Gene Expression / drug effects
  • HeLa Cells
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / immunology*
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Interferon-gamma / pharmacology
  • Iron / metabolism*
  • K562 Cells
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • MCF-7 Cells
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Receptor Coactivators / genetics
  • Nuclear Receptor Coactivators / metabolism
  • RNA Interference
  • Siderophores / pharmacology

Substances

  • Histocompatibility Antigens Class I
  • NcoA4 protein, mouse
  • Nuclear Receptor Coactivators
  • Siderophores
  • Interferon-gamma
  • Apoferritins
  • Iron
  • Deferoxamine