title: A role for HLA-DO as a co-chaperone of HLA-DM in peptide loading of MHC class II molecules.
abstract: In B cells, the non-classical human leukocyte antigens HLA-DO (DO) and HLA-DM (DM) are residents of lysosome-like organelles where they form tight complexes. DM catalyzes the removal of invariant chain-derived CLIP peptides from classical major histocompatibility complex (MHC) class II molecules, chaperones them until peptides are available for loading, and functions as a peptide editor. Here we show that DO preferentially promotes loading of MHC class II molecules that are dependent on the chaperone activity of DM, and influences editing in a positive way for some peptides and negatively for others. In acidic compartments, DO is engaged in DR-DM-DO complexes whose physiological relevance is indicated by the observation that at lysosomal pH DM-DO stabilizes empty class II molecules more efficiently than DM alone. Moreover, expression of DO in a melanoma cell line favors loading of high-stability peptides. Thus, DO appears to act as a co-chaperone of DM, thereby controlling the quality of antigenic peptides to be presented on the cell surface.
authors.affiliation: German Cancer Research Center, Department of Molecular Immunology, Heidelberg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Kropshofer
authors.forename: A B
authors.initials: AB
authors.lastname: Vogt
authors.forename: C
authors.initials: C
authors.lastname: Thery
authors.forename: E A
authors.initials: EA
authors.lastname: Armandola
authors.forename: B C
authors.initials: BC
authors.lastname: Li
authors.forename: G
authors.initials: G
authors.lastname: Moldenhauer
authors.forename: S
authors.initials: S
authors.lastname: Amigorena
authors.forename: G J
authors.initials: GJ
authors.lastname: Hämmerling
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D015536:Down-Regulation / Q000276:immunology; D006681:HLA-D Antigens / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D006684:HLA-DR Antigens / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008545:Melanoma / Q000235:genetics; D051379:Mice; D018832:Molecular Chaperones / Q000502:physiology*; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
chemical_list: C416186:H-2O antigen; C416189:H2-M antigens; D006681:HLA-D Antigens; C084245:HLA-DM antigens; C046148:HLA-DO antigens; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D018832:Molecular Chaperones; D010455:Peptides; D011994:Recombinant Proteins