Invariant chain

After synthesis in the rough ER, MHC class II α and β chains associate with the invariant chain, forming a nonameric complex. The invariant chain serves three main functions: (1) it stabilizes the MHC II peptide-binding groove and prevents binding of endogenous ER peptides (which are instead loaded onto MHC I), (2) it directs trafficking of the MHC II complex from the ER through the Golgi to the MIIC (MHC class II compartment, an endosomal/lysosomal vesicle), and (3) it is sequentially degraded by proteases (cathepsins) in the acidified endosome, leaving a small fragment called CLIP (Class II-associated Invariant chain Peptide) still bound in the groove. HLA-DM then catalyzes the exchange of CLIP for antigenic peptides derived from exogenous proteins that have been endocytosed and processed in the endosomal pathway. This ensures MHC II molecules present extracellular/phagocytosed antigens to CD4+ T helper cells, maintaining the fundamental separation between the MHC I (endogenous/cytosolic antigen, CD8+ T cell) and MHC II (exogenous antigen, CD4+ T cell) presentation pathways. Clinically, defects in invariant chain processing or HLA-DM function can impair antigen presentation and are relevant in understanding autoimmune disease mechanisms and vaccine design. CD74 (invariant chain) is also notably overexpressed in certain B-cell lymphomas and is a target of some therapeutic antibodies (e.g., milatuzumab).