title: The WT hemochromatosis protein HFE inhibits CD8⁺ T-lymphocyte activation.
abstract: MHC class I (MHC I) antigen presentation is a ubiquitous process by which cells present endogenous proteins to CD8(+) T lymphocytes during immune surveillance and response. Hereditary hemochromatosis protein, HFE, is involved in cellular iron uptake but, while structurally homologous to MHC I, is unable to bind peptides. However, increasing evidence suggests a role for HFE in the immune system. Here, we investigated the impact of HFE on CD8(+) T-lymphocyte activation. Using transient HFE transfection assays in a model of APCs, we show that WT HFE (HFEWT ), but not C282Y-mutated HFE, inhibits secretion of MIP-1β from antigen-specific CD8(+) T lymphocytes. HFEWT expression also resulted in major decreases in CD8(+) T-lymphocyte activation as measured by 4-1BB expression. We further demonstrate that inhibition of CD8(+) T-lymphocyte activation was independent of MHC I surface levels, β2-m competition, HFE interaction with transferrin receptor, antigen origin, or epitope affinity. Finally, we identified the α1-2 domains of HFEWT as being responsible for inhibiting CD8(+) T-lymphocyte activation. Our data imply a new role for HFEWT in altering CD8(+) T-lymphocyte reactivity, which could modulate antigen immunogenicity.
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) Institut du cancer de Montréal, Montréal, Québec, Canada; Département de Médecine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Reuben
authors.forename: Mikaël
authors.initials: M
authors.lastname: Phénix
authors.forename: Manuela M
authors.initials: MM
authors.lastname: Santos
authors.forename: Réjean
authors.initials: R
authors.lastname: Lapointe
mesh_terms: D019943:Amino Acid Substitution; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D057809:HEK293 Cells; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000276:immunology
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; C505714:TNFRSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
keywords: Antigen presentation; HFE; MHC I; T-cell activation