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The non-classical Major Histocompatibility Complex class II (MHCII) protein, H2-M, edits peptides bound to conventional MHCII in favor of stable peptide/MHCII (p/MHCII) complexes. Here, we show that H2-M deficiency affects B-1 cell survival, reduces cell renewal capacity, and alters immunoglobulin repertoire, allowing for the selection of cells specific for highly abundant epitopes, but not low-frequency epitopes. H2-M-deficient B-1 cells have shorter CDR3 length, higher content of positively charged amino acids, shorter junctional regions, less mutation frequency, and a skewed clonal distribution. Mechanistically, H2-M loss reduces plasma membrane p/MHCII association with B cell receptors (BCR) on B-1 cells and diminishes integrated BCR signal strength, a key determinant of B-1 cell selection, maturation, and maintenance. Thus, H2-M:MHCII interaction serves as a cell-intrinsic regulator of BCR signaling and influences the selection of the B-1 cell clonal repertoire. [Display omitted] • H2-M deficiency reduces B-1a cell self-renewal and cell survival • Lack of H2-M:MHCII interaction leads to a neonatal-like B-1a cell clonal repertoire • H2-M loss reduces plasma membrane association of p/MHCII with BCRs • H2-M selection of MHCII peptide cargo regulates BCR signalosome signal intensity H2-M is an MHCII peptide editor that selects for stable peptide-MHCII complexes. Ghosh et al. show that H2-M loss reduces plasma membrane p/MHCII:BCR association and BCR signal strength, highlighting a mechanism by which B-1a cell clonal selection and development directly depend on the functional association of H2-M with MHCII. [ABSTRACT FROM AUTHOR]

HLA-DO (H2-O in mice) is a nonpolymorphic transmembrane αβ heterodimer encoded in the class II region of the major histocompatibility complex (MHC). It is expressed selectively in B lymphocytes and thymic medullary epithelial cells. DO forms a stable complex with the peptide-loading catalyst HLA-DM in the endoplasmic reticulum (ER); in the absence of DM, DO is unstable. During intracellular transport and distribution in the endosomal compartments, the ratio of DO to DM changes. In primary B cells, only approx 50% of DM molecules are associated with DO. DO appears to regulate the peptide-loading function of DM in the MHC class II antigen-presentation pathway. Although certain di screpancies are present, results from most studies indicate that DO (as well as H2-O) inhibits DM (H2-M) function; this inhibition is pH-dependent. As a consequence, DO restrains presentation of exogenous antigens delivered through nonreceptor-mediated mechanisms, in addition, DO alters the peptide repertoire that is associated with cell-surface class II molecules. The biological function of DO remains obscure, partially because of the lack of striking phenotypes in the H2-O knockout mice. Results from recent studies indicate that DO expression in B cells is dynamic, and highly regulated during B-cell development and B-cell activation, suggesting that the physiological role of DO is to tailor the antigen presentation function of the B-line age cells to meet their primary function at each stage of B-cell development and maturation. Further investigations are needed in this direction. [ABSTRACT FROM AUTHOR]

H2-M is a major histocompatibility complex (MHC) class II-like molecule that catalyzes peptide binding to MHC class II molecules. Recently, the H2-O heterodimer, encoded by H2-Oa and H2-Ob in the MHC class II region, has been shown to be physically associated with H2-M in B cells and to downregulate H2-M function. Examination of H2-O expression in freshly isolated mouse organs revealed that H2-Oa- and H2-Ob-specific transcripts are present in both lymphoid and nonlymphoid tissues. To evaluate the gene regulation and functional impact of H2-O on antigen presentation, we examined the effects on MHCII, invariant chain (Ii), H2-M, and H2-O gene expression of interleukin (IL)-4, IL-10, and interferon (IFN)-γ in different antigen-presenting cells (APCs). In nonprofessional APCs, e.g., L929 fibroblasts, IFN-γ-inducible expression of the MHC class II-specific transcription factor CIITA is associated with coordinate expression of MHCII, Ii, H2-M, and H2-Oa genes but without concomitant H2-Ob induction. In contrast, professional APCs, e.g., the macrophage cell line P388D1, exhibit constitutive H2-Oa and H2-Ob expression, which is not inducible by IFN-γ in contrast to CIITA, MHCII, Ii, and H2-M expression. In B cells, CIITA, MHCII, Ii, and H2-M genes are differentially expressed relative to H2-Oa and H2-Ob genes upon stimulation with IL-4, IL-10, or IFN-γ. A differential ratio of H2-M to H2-O may represent one mechanism by which professional and nonprofessional APCs bypass H2-O inhibitory activity. [ABSTRACT FROM AUTHOR]