In the presence of a mixture of peptides capable of binding to MHC class II molecules, HLA-DM continuously binds and rebinds to newly formed peptide:MHC class II complexes, allowing for the dissociation of weakly bound peptides and for other peptides to replace them. Antigens presented by MHC class II molecules may have to persist on the surface of antigen-presenting cells for some days before encountering T cells able to recognize them. The ability of HLA-DM to remove unstably bound peptides, sometimes called peptide editing (see Section 6-4), ensures that the peptide:MHC class II complexes displayed on the surface of the antigen-presenting cell survive long enough to stimulate the appropriate CD4 T cells. During this process, it is likely that some peptides are captured first as longer polypeptides that undergo amino-terminal trimming by exopeptidases, further increasing the number of possible peptides that can be bound.
A second atypical MHC class II molecule, called HLA-DO in humans (H-2O in mice), is produced in thymic epithelial cells, B cells, and dendritic cells.
MOVIE 6.2
Invariant chain (Ii) forms a complex with MHC class II molecule, blocking the binding of peptides and misfolded proteins Ii is cleaved in an acidifed endosome, leaving a short peptide fragment, CLIP, still bound to the MHC class II molecule Endocytosed antigens are degraded to peptides in endosomes, but the CLIP peptide blocks the binding of peptides to MHC class II molecules HLA-DM binds to the MHC class II molecule, releasing CLIP and allowing other peptides to bind. The MHC class II molecule then travels to the cell surface HLA-DM endoplasmic reticulum cytosol Ii LIP10 CLIP
Fig. 6.13 HLA-DM facilitates the loading of antigenic peptides leaving CLIP bound to the MHC class II molecules. Third panel: onto MHC class II molecules. First panel: the invariant chain pathogens and their proteins are broken down into peptides within (Ii) binds to newly synthesized MHC class II molecules and blocks acidified endosomes, but these peptides cannot bind to MHC peptides from binding class II molecules in the endoplasmic class II molecules that are occupied by CLIP. Fourth panel: the class reticulum and during their transport to acidified endosomes. Second II-like molecule HLA-DM binds to MHC class II:CLIP complexes, panel: in late endosomes, proteases cleave the invariant chain, catalyzing the release of CLIP and the binding of antigenic peptides.
Fig. 6.14 HLA-DM and HLA-DO regulate loading of peptides into MHC class II molecules. First panel: the HLA-DM dimer, composed of α (green) and β (turquoise) chains, binds to the HLA-DR MHC class II molecule (side view). HLA-DM contacts the MHC molecule near the peptide-binding groove where the peptide amino terminus would reside. Second panel: HLA-DO binds to HLA-DM in a similar configuration as HLA-DR, thus blocking DM’s peptide-editing activity. Third panel: top view of HLA-DR with bound peptide in the absence of HLA-DM. Fourth panel: top view of HLA-DR with HLA-DM bound. The amino-terminal end of the MHC peptide-binding groove is open and devoid of bound peptide, enabling peptide exchange.