HFE cross-talks with the MHC class I antigen presentation pathway.
HFE is a protein known to be involved in iron metabolism; yet, other than its homology with major histocompatibility complex (MHC) class I molecules, it has not been described as having an immunologic function. Here we report that peripheral blood mononuclear cells (PBMCs) from patients with hereditary hemochromatosis (HH) carrying the C282Y mutation in HFE have reduced cell-surface expression of MHC class I due to an enhanced endocytosis rate of MHC class I molecules caused by premature peptide and beta2-microglobulin dissociation. This faster turnover also leads to increased expression levels of cell-surface free class I heavy chains in mutant PBMCs. Biochemical analysis indicates an earlier peptide loading and endoplasmic reticulum maturation of MHC class I molecules in C282Y mutant cells. Thermostability assays further showed that in HFE mutants the MHC class I peptide loading gives rise to low-stability heterotrimers that dissociate prematurely during its intracellular traffic. The present results suggest the existence of an intriguing cross-talk between a particular HFE mutation and the classical MHC class I route. These findings constitute the first description of peptide presentation pathway abnormalities linked to HFE and provide additional evidence for the occurrence of immunologic defects in patients with HH.
de Almeida
Sérgio F
SF
Iron Genes and Immune System, IBMC, Rua do Campo Alegre 823, 4150-180 Porto, Portugal.
Carvalho
Isabel F
IF
Cardoso
Carla S
CS
Cordeiro
João V
JV
Azevedo
Jorge E
JE
Neefjes
Jacques
J
de Sousa
Maria
M
D017951:Antigen Presentation / Q000235:genetics*; D004705:Endocytosis; D006432:Hemochromatosis / Q000276:immunology; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism*; D020125:Mutation, Missense; D020239:Receptor Cross-Talk / Q000276:immunology*; D013462:Sulfur Radioisotopes
C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D013462:Sulfur Radioisotopes