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) cl ass II molecules, chaperones them until peptides are available for loa ding, and functions as a peptide editor. Here we show that DO preferen tially promotes loading of MHC class II molecules that are dependent o n the chaperone activity of DMI, and influences editing in a positive way for some peptides and negatively for others. In acidic compartment s, DO is engaged in DR-DM-DO complexes whose physiological relevance i s indicated by the observation that at lysosomal pH DM-DO stabilizes e mpty class II molecules more efficiently than DM alone. Moreover, expr ession 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 con trolling the quality of antigenic peptides to be presented on the cell surface.