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.
Major histocompatibility complex (MHC) class II αβ heterodimers bind peptides generated by degradation of endocytosed antigens and display them on the cell surface of antigen-presenting cells (APCs) for CD4+ T-cell recognition. Newly synthesized class II α and β chains associate in the endoplasmic reticulum (ER) with a third glycoprotein, the invariant chain (Ii), which prevents premature peptide binding to MHC class II molecules and facilitates MHC class II transport from the ER into specialized compartments of the endocytic pathway collectively termed MIIC, where peptide loading occurs. There, Ii is cleaved by proteolysis resulting in a nested set of peptides, termed CLIP, for MHC class II-associated invariant peptides which bind to the peptide-binding groove of MHC class II molecules. CLIP is finally exchanged for antigenic peptides by the catalytic action of an MHC class II-like heterodimeric molecule designated H2-M in the mouse and HLA-DM (DM) in humans. H2-M/DM is selectively targeted to MHC class II-containing endocytic compartments and a transient interaction between H2-M/DM and MHC class II molecules appears to induce a conformational state that favors replacement of CLIP with antigenic peptides. Mouse or human cell lines carrying mutations in H2-M or DM genes exhibit impaired presentation of exogenous protein antigens and express MHC class II molecules preferentially occupied by CLIP.
In B cells, H2-M/DM forms stable complexes with a second heterodimeric molecule termed H2-O in the mouse and HLA-DO (DO) in humans. The H2-O (DO) heterodimer consists of an α and β chain encoded by the H2-Oa (DOA) and H2-Ob (DOB) genes within the MHC class II region. DO is a resident of MIICs and has been shown to inhibit the ability of DM to catalyze peptide loading onto different MHC class II molecules. A detailed analysis using B cells from H2-O-deficient mice revealed that H2-O selectively prevents the presentation of antigens that are internalized by fluid-phase endocytosis. This leads to preferential presentation of antigens that are internalized through the membrane immunoglobulin receptor.
Transcriptional activation of MHCII, H2-M/DM and Ii genes appears to be controlled by the MHC class II transactivator CIITA, whereas transcription of H2-O/DO genes was found to be CIITA independent.