peptide loading of MHC class II molecules

equally to this work 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 com-plexes. DM catalyzes the removal of invariant chain-derived CLIP peptides from classical major histocom-patibility complex (MHC) class II molecules, chap-erones 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 com-plexes 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