H2-O does not preempt autoimmunity but controls murine γherpesvirus MHV68

H2-O (human HLA-DO) is a relatively conserved non-classical Major Histocompatibility Class II (MHCII)-like molecule. H2-O interaction with H2-M (human HLA-DM) edits the repertoire of peptides presented to T cell receptors by MHCII. It was long hypothesized that H2-M inhibition by H2-O provides protection from autoimmunity by preventing binding of the high affinity self-peptides to MHCII. The available evidence supporting this hypothesis, however, was inconclusive. A possibility still remained that the effect of H2-O-deficiency on autoimmunity could be better revealed by using H2-O-deficient mice that were already genetically predisposed to autoimmunity. Here, we generated and used autoimmunity-prone mouse models for systemic lupus erythematosus and organ-specific autoimmunity (Type 1 diabetes and multiple sclerosis) to definitively test whether H2-O prevents autoimmune pathology. Whereas our data failed to support any significance of H2-O in protection from autoimmunity, we found that it was critical for controlling a γherpesvirus, MHV68. Thus, we propose that H2-O editing of MHCII peptide repertoire may have evolved as a safeguard against specific highly prevalent viral pathogens.