HLA class II histocompatibility antigen gamma chain also known as HLA-DR antigens-associated invariant chain or CD74 (Cluster of Differentiation 74), is a protein that in humans is encoded by the CD74gene.[5][6] The invariant chain (Abbreviated Ii) is a polypeptide which plays a critical role in antigen presentation. It is involved in the formation and transport of MHC class II peptide complexes for the generation of CD4+ T cell responses.[7][8] The cell surface form of the invariant chain is known as CD74. CD74 is a cell surface receptor for the cytokine macrophage migration inhibitory factor (MIF).[9]
Function
The nascent MHC class II protein in the rough endoplasmic reticulum (RER) binds a segment of the invariant chain (Ii; a trimer) in order to shape the peptide-binding groove and prevent the formation of a closed conformation.
The invariant chain also facilitates the export of MHC class II from the RER in a vesicle. The signal for endosomal targeting resides in the cytoplasmic tail of the invariant chain. This fuses with a late endosome containing the endocytosed antigen proteins (from the exogenous pathway). Binding to Ii ensures that no antigen peptides from the endogenous pathway meant for MHC class I molecules accidentally bind to the groove of MHC class II molecules.[10] The Ii is then cleaved by cathepsin S (cathepsin L in cortical thymic epithelial cells), leaving only a small fragment called CLIP remaining bound to the groove of MHC class II molecules. The rest of the Ii is degraded.[10] CLIP blocks peptide-binding until HLA-DM interacts with MHC II, releasing CLIP and allowing other peptides to bind. In some cases, CLIP dissociates without any further molecular interactions, but in other cases the binding to the MHC is more stable.[11]
The stable MHC class II + antigen complex is then presented on the cell surface. Without CLIP, MHC class II aggregates disassemble and/or denature in the endosomes, and proper antigen presentation is impaired.[12]
Clinical significance
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.[13]
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).[14]
Cancer
Found on a number of cancer cell types. Possible cancer therapy target. See milatuzumab.
Role of CD74 receptor in tissue injury and wound repair
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.[22]
History
The invariant chain was first described by Patricia P. Jones, Donal B. Murphy, Derek Hewgill, and Hugh McDevitt at Stanford.[23] The nomenclature "Ii" comes from an Ix-based naming system (I for Immune) that predates the naming of the Major Histocompatibility Complex.
^Vogt AB, Kropshofer H (April 1999). "HLA-DM - an endosomal and lysosomal chaperone for the immune system". Trends in Biochemical Sciences. 24 (4): 150–154. doi:10.1016/s0968-0004(99)01364-x. PMID10322421.
^
Shan ZX, Lin QX, Deng CY, Tan HH, Kuang SJ, Xiao DZ, et al. (December 2009). "[Identification of the interactions between the truncated fragments of macrophage migration inhibitory factor and CD74 using a yeast two-hybrid system]". Nan Fang Yi Ke da Xue Xue Bao = Journal of Southern Medical University (in Chinese). 29 (12): 2383–6, 2390. PMID20034881.
^Wang F, Shen X, Guo X, Peng Y, Liu Y, Xu S, Yang J (February 2010). "Spinal macrophage migration inhibitory factor contributes to the pathogenesis of inflammatory hyperalgesia in rats". Pain. 148 (2): 275–283. doi:10.1016/j.pain.2009.11.011. PMID20005040. S2CID38141283.
^Jones PP, Murphy DB, Hewgill D, McDevitt HO (January 1979). "Detection of a common polypeptide chain in I--A and I--E sub-region immunoprecipitates". Molecular Immunology. 16 (1): 51–60. doi:10.1016/0161-5890(79)90027-0. PMID376435.
Genuardi M, Saunders GF (1988). "Localization of the HLA class II-associated invariant chain gene to human chromosome band 5q32". Immunogenetics. 28 (1): 53–56. doi:10.1007/BF00372530. PMID3132422. S2CID2418453.
Koch N, Hämmerling GJ (October 1985). "Ia-associated invariant chain is fatty acylated before addition of sialic acid". Biochemistry. 24 (22): 6185–6190. doi:10.1021/bi00343a023. PMID3866610.
Claesson L, Peterson PA (June 1983). "Association of human gamma chain with class II transplantation antigens during intracellular transport". Biochemistry. 22 (13): 3206–3213. doi:10.1021/bi00282a026. PMID6576808.
Machamer CE, Cresswell P (December 1982). "Biosynthesis and glycosylation of the invariant chain associated with HLA-DR antigens". Journal of Immunology. 129 (6): 2564–2569. doi:10.4049/jimmunol.129.6.2564. PMID6982931. S2CID42620266.
Brown JH, Jardetzky TS, Gorga JC, Stern LJ, Urban RG, Strominger JL, Wiley DC (July 1993). "Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1". Nature. 364 (6432): 33–39. Bibcode:1993Natur.364...33B. doi:10.1038/364033a0. PMID8316295. S2CID4248668.
Naujokas MF, Morin M, Anderson MS, Peterson M, Miller J (July 1993). "The chondroitin sulfate form of invariant chain can enhance stimulation of T cell responses through interaction with CD44". Cell. 74 (2): 257–268. doi:10.1016/0092-8674(93)90417-O. PMID8343954. S2CID10295196.
