DescriptionThe MHC class II antigen presentation pathway acts as a bridge between the innate and adaptive immune responses. HLA molecules of the MHC class II (MHCII) bind and present pathogen-derived peptides for CD4 T cell activation. Peptide loading of MHCII in the endosomes of cells is controlled by the interplay of the nonclassical MHCII molecules, HLA-DM (DM) and HLA-DO (DO). DM catalyzes peptide loading, whereas DO, an MHCII substrate mimic, prevents DM from interacting with MHCII, resulting in an altered MHCII-peptide repertoire and increased MHCII-CLIP. Previous studies from our lab revealed that the mouse homolog of DO, H2-O, blocks a neutralizing antibody response to a retrovirus. We investigated the effect of H2-O deficiency on immune function in mice. Interestingly, we found an increase in immune cell activation in the small intestines of H2-O deficient mice. These changes appeared to dissipate as the mice aged. Our previous study also found naturally occurring variants of the gene that encodes the beta chain of DO, DOB, that altered DO function. A more functional variant of DOB was linked to individuals who struggle to neutralize Hepatitis C virus. We have now analyzed naturally occurring variants of the gene that encodes the alpha chain of DO, DOA, and found several with altered function. In fact, 52% of the variants analyzed altered DO function, two of which were linked to Hepatitis B viral immune responses. A more functional variant, DOA*0102, was linked to Hepatitis B viral persistence. A functionally null variant, DOalpha F114L, was conversely linked to Hepatitis B viral clearance. Further characterization of the gain-of-function variants identified in this study suggests that the mechanism of DO’s inhibitory function of DM is more complex than previously understood. DO binding to DM may permanently alter DM’s functional capability, even if DO is no longer bound to DM.