9.A.75.  The MHC II Receptor (MHC2R) Family 

This family consists of a complex of 3 proteins, DQ α-1, DQ β-1, which together comprise a heterodimer, and CD74, a homotrimer that forms a nanomeric complex with three DQ α/β dimers.  CD74 plays a role in MHC class II antigen processing by stabilizing the peptide-free class II alpha/beta heterodimers in a complex soon after their synthesis, and directing transport of the complex from the endoplasmic reticulum to the endosomal/lysosomal system where the antigen processing and binding of antigenic peptides to MHC class II (DG α-1/DG β-1) takes place. CD74 also serves as cell surface receptor for the cytokine MIF.  MHC II binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. The removal of the CD74-derived CLIP peptide is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO (Jiang et al. 2019; Santambrogio et al. 2019; Jurewicz and Stern 2019; Dijkstra and Yamaguchi 2019).

As noted above, an alpha and a beta subunit, also referred as MHC class II molecule, forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases, leaving a small fragment termed CLIP  (see above) on each MHC class II molecule. An MHC class II molecule interacts with HLA_DM, and HLA_DO in the B-cells, in order to release CLIP and facilitate the binding of antigenic peptides (Lee et al. 2001; Siebold et al. 2004; Kim et al. 2004; Henderson et al. 2007).