The impact of the non-classical MHC proteins HLA-DM and HLA-DO on loading of MHC class II molecules

Peptide binding to classical major histocompatibility complex (MHC) class I I molecules is known to be determined by the properties of the class II pep tide binding groove but recently it turned out to be co-controlled by the a ctivity of the non-classical MHC molecules HLA-DM and HLA-DO: HLA-DM functi ons as a mediator of peptide exchange. In addition, HLA-DM is a chaperone f or MHC class II molecules in endosomal and lysosomal loading compartments b ecause it stabilizes the empty MHC class II peptide binding groove and keep s it receptive for peptide loading until appropriate peptide ligands are ca ptured. Since HLA-DM favors the generation of high-stability peptide-MHC cl ass II complexes by releasing low-stability peptide ligands, DM activity af fects the peptide repertoire presented on the cell surface of antigen-prese nting cells. HLA-DO is expressed mainly in B cells and binds tightly to HLA -DM thereby modulating its activity. Together, HLA-DM and HLA-DO are critic al factors in shaping the MHC class II-associated self or foreign peptide r epertoire of antigen presenting cells and, hence, govern initiation or prev ention of an immune response.