HLA-DM acts as a molecular chaperone and rescues empty HLA-DR molecules at lysosomal pH

HLA-DM (DM) is a nonclassical MHC class II molecule that interacts with classical MHC II molecules in acidic compartments. During this association DM is supposed to catalyze the release of invariant chain (li)derived CLIP peptides, as well as other peptides bound with low kinetic stability. Here we provide evidence that in lysosomal compartments of B cells a considerable fraction of DM is stably associated with empty DR alpha beta dimers, thereby preventing their functional inactivation and aggregation. Upon encounter with cognate peptide, the DM-associated DR molecules can be rapidly loaded and no longer bind to DM. Thus, DM seems to act as a dedicated class Ii-specific chaperone. In view of the suggested shortage of DM-resistant self-peptides in the loading compartment, empty class II molecules that are chaperoned by DM may enable the antigen-processing system to respond promptly to the challenge by newly entering antigens.