H2-O deficiency is associated with altered intestinal bacterial communities and differential IgG binding

The non-classical major histocompatibility complex class II (MHCII) molecule H2-O regulates peptide loading by inhibiting H2-M, thereby restricting the repertoire of high-affinity peptides presented to CD4 + T cells. H2-O deficiency enhances protective immunoglobulin G (IgG) responses against pathogens, including retroviruses and Staphylococcus aureus , and promotes the generation of IgG specific for the commensal bacterium Staphylococcus xylosus . Whether these expanded antibody responses influence intestinal microbial communities is unknown. Here, using gnotobiotic mouse models, we demonstrate that H2-O shapes the gut bacterial composition to a limited but significant extent. H2-O deficiency was associated with increased serum IgG reactivity against commensal microbial antigens (Ags). Sequencing antibody-coated bacteria revealed distinct populations between H2-O-deficient and H2-O-sufficient mice within the IgG-coated, but not IgA-coated, fractions. Together, these findings identify an association between H2-O genotype and microbiome composition and reveal differential IgG, but not IgA, binding to intestinal bacterial communities. These results expand current understanding of how Ag presentation pathways influence host-microbiome interactions and suggest a potential relationship between regulation of the MHCII peptidome, IgG responses, and commensal ecology. IMPORTANCE Our findings demonstrate that the absence of H2-O not only promotes protective IgG responses against retroviruses and Staphylococcus aureus but also is associated with altered intestinal IgG binding patterns and differences in gut microbiome composition.