MHC Class II presentation is affected by polymorphism in the H2-Ob gene and additional loci

Pathogen-derived peptides are loaded on MHC class II (MHCII) and presented to CD4+ T cells for their activation. Peptide loading of MHCII occurs in specialized endosomal compartments and is controlled by the nonclassical MHCII molecules H2-M and H2-O, which are both constitutive αβ heterodimers. H2-M catalyzes MHCII peptide loading, whereas H2-O modulates H2-M activity by acting as an MHCII mimic. Recently, we discovered that the H2-Ob allele inherited by retrovirus-resistant I/LnJ mice results in nonfunctional H2-O. I/LnJ H2-O binds to but does not inhibit H2-M. Compared with H2-Ob from virus-susceptible mice, H2-Ob from I/LnJ mice has four unique amino acid substitutions, three in the Ig domain and one in the cytoplasmic tail. In this study we show that the three amino acids in the Ig domain of I/LnJ Ob are critical for the H2-O inhibitory activity of H2-M. Unexpectedly, we found that MHCII presentation was significantly different in Ag-presenting cells from two closely related mouse strains, B6J and B6N, which carry identical alleles of MHCII, H2-O, and H2-M. Using a positional cloning approach, we have identified two loci, polymorphic between B6J and B6N, that mediate the difference in MHCII presentation. Collectively, these studies reveal extra complexity in MHCII/H2-M/H-2O interactions that likely involve yet to be identified modulators of the pathway. The Journal of Immunology, 2021, 207: 5-14.