To allow another peptide to bind to the MHC class II molecule, CLIP must either dissociate or be displaced. Newly synthesized MHC class II molecules are brought toward the cell surface in vesicles, most of which at some point fuse with incoming endosomes. However, some MHC class II:Ii complexes may first be transported to the cell surface and reinternalized into endosomes. In either case, MHC class II:Ii complexes enter the endosomal pathway, where they encounter and bind peptides derived from either internalized pathogen proteins or self proteins. Initially, specialized endosomal compartments were thought to exist for antigen-presenting cells. One was an early endosomal compartment in dendritic cells that was called the CIIV (MHC class II vesicle). Another, a late endosomal compartment containing Ii and MHC class II molecules, was the MHC class II compartment, or MIIC (Fig. 6.12). The current view is that MHC class II molecules use many common endocytic compartments, including lysosomes, to allow for the exchange of CLIP for as many peptides as possible. MHC class II molecules that do not bind peptide after dissociation from CLIP are unstable in the acidic pH after fusion with lysosomes, and they are rapidly degraded.
6-8 The MHC class II-like molecules HLA-DM and HLA-DO regulate exchange of CLIP for other peptides.
Because an MHC class II:CLIP complex cannot be released to the cell surface unless another peptide replaces it, antigen-presenting cells possess a mechanism that facilitates the efficient exchange of CLIP for other peptides. This process was uncovered by analysis of mutant human B-cell lines with a defect in antigen presentation. MHC class II molecules in these mutant cells assemble correctly with Ii and seem to follow the normal vesicular route, but fail to bind peptides derived from internalized proteins and often arrive at the cell surface with the CLIP peptide still bound. The defect in these cells lies in an MHC class II-like molecule called HLA-DM in humans (H-2DM in mice). The HLA-DM genes (see Section 6-10) are found near the TAP and PSMB8/9 genes in the MHC class II region (see Fig. 6.16); they encode an α chain and a β chain that closely resemble those of other MHC class II molecules. The HLA-DM molecule is not present at the cell surface, however, but is found predominantly in the endosomal compartment that contains Ii and MHC class II molecules. HLA-DM binds to and stabilizes empty MHC class II molecules and catalyzes the release of CLIP, thus allowing the binding of other peptides to the empty MHC class II molecule (Fig. 6.13). The HLA-DM molecule does not contain the open groove found in other MHC class II molecules, and it does not bind peptides. Instead, HLA-DM binds to the α chain of the MHC class II molecule near the region of the floor of the peptide-binding site (Fig. 6.14). This binding induces changes in the structure of the MHC class II molecule, and holds this part of the peptide binding groove in a partially ‘open’ configuration (see Fig. 6.14, right panel). In this way, HLA-DM catalyzes the release of CLIP and of other unstably bound peptides from MHC class II molecules.