CD74

CD74, also known as the MHC class II invariant chain (Ii), is a type II transmembrane glycoprotein expressed mainly by antigen-presenting cells such as B lymphocytes, dendritic cells, and macrophages. The CD74 gene encodes several isoforms produced by alternative translation initiation, including p41 and p35, which differ in their luminal extensions.

In the endoplasmic reticulum, CD74 binds newly synthesized MHC class II α and β chains, acting as a chaperone and blocking peptide binding to prevent premature loading. It directs the complex to endosomal compartments where the invariant chain is proteolytically processed, leaving CLIP in the peptide-binding groove. HLA-DM then facilitates exchange of CLIP for antigenic peptides before transport to the cell surface for presentation to CD4+ T cells.

CD74 also functions as a receptor for macrophage migration inhibitory factor (MIF) and other ligands. Through CD74, cells can activate signaling pathways such as ERK1/2 and PI3K/AKT, influencing survival, differentiation, and immune responses. The invariant chain can form complexes with CD44 in signaling, and CD74 signaling can occur in cells beyond classic antigen-presenting cells and in various cancers.

Clinically, CD74 serves as a marker for B cells in flow cytometry and immunohistochemistry and is explored as a therapeutic target. Milatuzumab, a humanized anti-CD74 antibody, has been evaluated in hematologic malignancies and some solid tumors. Aberrant CD74 expression has been observed in certain autoimmune conditions and tumors, reflecting its diverse roles in immunity and disease.