The ability of pathogens to sequester iron from their host cells and proteins affects theirvirulence. Moreover, iron is required for various innate host defense mechanisms aswell as for acquired immune responses. Therefore, intracellular iron concentration mayinfluence the interplay between pathogens and immune system. Here, we investigatedwhether 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 primarycancer cells and macrophages. On the contrary, mouse embryonic fibroblasts (MEFs)from NCOA4 null mice accumulated FTH for ferritinophagy impairment and displayedMHC class I cell surface overexpression. Low iron concentration, but not FTH, interferedwith IFN-γ receptor signaling, preventing the increase of MHC-class I molecules on themembrane by obstructing STAT1 phosphorylation and nuclear translocation. Finally, irondepletion and FTH downregulation increased the target susceptibility of both primarycancer cells and macrophages to NK cell recognition. In conclusion, the reduction ofiron and FTH may influence the expression of MHC class I molecules leading to NKcells activation.
Iron and Ferritin Modulate MHC Class I Expression and NK Cell Recognition.
Garofalo C;Quaresima B;Cristiani CM;Perrotti N;Faniello C;Cuda G;Costanzo F;Carbone E
2019-01-01
Abstract
The ability of pathogens to sequester iron from their host cells and proteins affects theirvirulence. Moreover, iron is required for various innate host defense mechanisms aswell as for acquired immune responses. Therefore, intracellular iron concentration mayinfluence the interplay between pathogens and immune system. Here, we investigatedwhether 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 primarycancer cells and macrophages. On the contrary, mouse embryonic fibroblasts (MEFs)from NCOA4 null mice accumulated FTH for ferritinophagy impairment and displayedMHC class I cell surface overexpression. Low iron concentration, but not FTH, interferedwith IFN-γ receptor signaling, preventing the increase of MHC-class I molecules on themembrane by obstructing STAT1 phosphorylation and nuclear translocation. Finally, irondepletion and FTH downregulation increased the target susceptibility of both primarycancer cells and macrophages to NK cell recognition. In conclusion, the reduction ofiron and FTH may influence the expression of MHC class I molecules leading to NKcells activation.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.