The MHC class II-like protein H2-O regulates B cell antigen presentation and germinal center entry

Antigen presentation on MHC class II (MHCII) is a vital process in the adaptive immune response. Antigen presenting cells (APCs) display peptides derived from both endogenous and exogenous sources on the cell surface for recognition by the T cell receptor (TCR) of CD4+ T cells. The TCR-peptide-MHCII interaction is important in the activation of both B cells and T cells. Peptides are loaded onto MHCII in the endosomal compartments of APCs. The peptide-loading process is catalyzed by the MHCII-like protein HLA-DM (H2-M in mice). This process is further modulated by another MHCII-like protein, HLA-DO (H2-O in mice). H2-O is a biochemical inhibitor of H2-M-mediated peptide loading, however on the cellular level it has been shown to have varying an effects on antigen presentation on MHCII depending on the antigen source and the peptide sequence. Thus the function of H2-O in vivo, as part of the adaptive immune response, remains unclear.;Here, we examine both the direct effect of H2-O on antigen presentation by antigen-specific B cells and the effect of H2-O expression on the ability of antigen specific B cells to enter the germinal center (GC). We show that H2-O inhibits antigen presentation in vivo shortly after immunization, even though this effect is not apparent when presentation of the same peptide is examined in vitro. Furthermore, we show that while wild type (WT) and H2-O -/- B cells can both independently form normal GCs, when they are placed in direct competition, H2-O-/- B cells are better able to enter the GC than WT B cells. This results in an increased expansion of the H2-O-/- population over the course of the immune response. This advantage is confined to antigen-specific B cells and is dependent on CD4+ T cells. Furthermore, it is due to their superior ability to gain antigen-specific T cell help from follicular helper T cells (TFH) in an environment where TFH are limiting. Together, these studies show that H2-O can inhibit loading of peptides derived from BCR-internalized antigens onto MHCII in B cells in vivo. More broadly, H2-O expression reduces the ability of B cells to gain T cell help and participate in the GC reaction.