A role for HLA-DO as a co-chaperone of HLA-DM in peptide loading of MHC class II molecules.
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.
Kropshofer
H
H
German Cancer Research Center, Department of Molecular Immunology, Heidelberg, Germany.
Vogt
A B
AB
Thery
C
C
Armandola
E A
EA
Li
B C
BC
Moldenhauer
G
G
Amigorena
S
S
Hämmerling
G J
GJ
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
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