The class II peptide editor, H2-M, affects the development and function of B-1 cells

Abstract

Abstract B-1 cells are known for their innate, polyreactive BCR repertoire, and proficiency at polarizing T cells towards inflammatory effector T cells, a critical component in host defense and autoimmunity. B-1 cells are antigen presenting cells (APCs) and express MHCII proteins to bind and display self and foreign peptides to CD4 T cells. H2-M edits peptide-MHCII complexes to ensure display of stably bound peptides by APCs. Absence of H2-M has most widely been studied for its impact on T cell activation, but knowledge of how this protein affects the development and function of APCs is lacking. We found that absence of H2-M down-regulated the surface expression and altered the distribution of MHCII molecules in B cells across lymphoid organs. Importantly, in H2-M KO mice, compared to the wild-type C57BL/6 (B6) mice, the frequency and abundance of B-1 cells, but not conventional B-2 cells was affected. Interestingly, the H2-M mediated effect on B-1 cell population was only evident in I-Ab expressing B6, not in Balb/c (I-Ad/I-Ed), indicating an MHCII haplotype dependent effect. Decrease in B-1 cell number was evident in both immature and mature B-1 cells, further indicating an H2-M mediated developmental defect of B-1 cells. In H2-M KO mice, B-1 cells display a significantly lower self-renewal capacity and higher rate of apoptosis compared to WT B6. Despite a lower total B-1 cell number, the frequency of B-1 cells specific for predominant self-antigens (like – phosphatidylcholine) is increased in H2-M KO mice, indicating skewing of B-1 BCR repertoire in absence of H2-M. Collectively, these data identify a novel impact of H2-M/MHCII interaction that regulates the development of B-1 cells and influences the selection of mature B-1 cell clones in the periphery.