CD74

The nascent MHC class II protein in the rough endoplasmic reticulum (RER) binds a segment of the invariant chain (Ii; a trimer), which shapes the peptide-binding groove and prevents the formation of a closed conformation. CD74 exists in several isoforms, most commonly p33, p35, p41, and p43, generated by alternative splicing and translation initiation sites. Isoforms p33/35 and p41/43 differ in the length of their luminal domains, with p41 and p43 containing an additional thyroglobulin-like region that influences proteolytic processing and MHC class II antigen presentation. Isoforms p35 and p43 also contain N-terminal extensions that enhance endoplasmic reticulum retention relative to p33 and p41.

The invariant chain facilitates the export of MHC class II molecules from the RER in transport vesicles. The signal for endosomal targeting resides in the cytoplasmic tail of the invariant chain, directing the complex to late endosomes containing endocytosed antigens from the exogenous pathway. Binding of the invariant chain prevents peptides from the endogenous pathway, which are destined for MHC class I molecules, from occupying the peptide-binding groove of MHC class II molecules.

The invariant chain is subsequently cleaved by cathepsin S (cathepsin L in cortical thymic epithelial cells), leaving only the CLIP fragment bound within the peptide-binding groove of MHC class II molecules, while the remainder of the invariant chain is degraded. CLIP prevents premature peptide binding until HLA-DM catalyzes its release, allowing antigenic peptides to bind. In some cases, CLIP dissociates spontaneously, whereas in others its interaction with MHC class II is sufficiently stable to require HLA-DM-mediated peptide exchange.

The resulting stable MHC class II-antigen complex is then presented on the cell surface for recognition by CD4⁺ T cells. In the absence of CLIP, MHC class II molecules aggregate, dissociate, or denature within endosomes, impairing efficient antigen presentation.

Vaccine adjuvant

The Ii molecule, fused with a viral vector to a conserved region of the Hepatitis C virus (HCV) genome, has been tested as an adjuvant for a HCV vaccine in a cohort of 17 healthy human volunteers. This experimental vaccine was well-tolerated, and those who received the adjuvanted vaccine had stronger anti-HCV immune responses (enhanced magnitude, breadth and proliferative capacity of anti-HCV-specific T-cells) compared with volunteers who received the vaccine that lacked the Ii adjuvant.

The Ii molecule might also prove to be useful as an adjuvant for a future vaccine for the SARS-CoV-2 virus, if this enhancing effect can be demonstrated to apply to the appropriate antigen(s).

Cancer

Found on a number of cancer cell types. Possible cancer therapy target. See milatuzumab.

Axial spondyloarthritis

Autoantibodies against CD74 have been identified as promising biomarkers in the early diagnosis of the autoimmune disease called axial spondyloarthritis (non-radiographic axial spondyloarthritis and radiographic axial spondyloarthritis / Ankylosing spondylitis).

CD74 receptor interacts with the cytokine Macrophage migration inhibitory factor (MIF) to mediate some of its functions.

CD74 receptor is expressed on the surface of different cell types. Interaction between MIF cytokine and its cell membrane receptor CD74 activates pro-survival and proliferative pathways that protect against injury and promote healing in different parts of the body.

The invariant chain was first described by Patricia P. Jones, Donal B. Murphy, Derek Hewgill, and Hugh McDevitt at Stanford. The nomenclature "Ii" comes from an Ix-based naming system (I for Immune) that predates the naming of the Major Histocompatibility Complex.