CD74 explained

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 CD74 gene.^{[1] [2]} 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.^{[3] [4]} 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).^[5]

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.^[6] 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. 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.^[7]

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.^[8]

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.^[9]

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).^[10]

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). ^[11]

Interactions

CD74 receptor interacts with the cytokine Macrophage migration inhibitory factor (MIF) to mediate some of its functions.^{[12] [13] [14] [15] [16] [17]}

Recovery 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.^[18]

History

The invariant chain was first described by Patricia P. Jones, Donal B. Murphy, Derek Hewgill, and Hugh McDevitt at Stanford.^[19] The nomenclature "Ii" comes from an Ix-based naming system (I for Immune) that predates the naming of the Major Histocompatibility Complex.

See also

• Cluster of differentiation
• Milatuzumab the first Mab to target CD74

References

Further reading

• Stove V, Verhasselt B . Modelling thymic HIV-1 Nef effects . Current HIV Research . 4 . 1 . 57–64 . January 2006 . 16454711 . 10.2174/157016206775197583 .
• Riberdy JM, Newcomb JR, Surman MJ, Barbosa JA, Cresswell P . HLA-DR molecules from an antigen-processing mutant cell line are associated with invariant chain peptides . Nature . 360 . 6403 . 474–477 . December 1992 . 1448172 . 10.1038/360474a0 . 4338656 . 1992Natur.360..474R .
• Bakke O, Dobberstein B . MHC class II-associated invariant chain contains a sorting signal for endosomal compartments . Cell . 63 . 4 . 707–716 . November 1990 . 2121367 . 10.1016/0092-8674(90)90137-4 . 19993336 .
• Marks MS, Blum JS, Cresswell P . Invariant chain trimers are sequestered in the rough endoplasmic reticulum in the absence of association with HLA class II antigens . The Journal of Cell Biology . 111 . 3 . 839–855 . September 1990 . 2391366 . 2116304 . 10.1083/jcb.111.3.839 .
• Spiro RC, Quaranta V . The invariant chain is a phosphorylated subunit of class II molecules . Journal of Immunology . 143 . 8 . 2589–2594 . October 1989 . 10.4049/jimmunol.143.8.2589 . 2507633 . 6755576 . free .
• O'Sullivan DM, Noonan D, Quaranta V . Four Ia invariant chain forms derive from a single gene by alternate splicing and alternate initiation of transcription/translation . The Journal of Experimental Medicine . 166 . 2 . 444–460 . August 1987 . 3036998 . 2189580 . 10.1084/jem.166.2.444 .
• Genuardi M, Saunders GF . Localization of the HLA class II-associated invariant chain gene to human chromosome band 5q32 . Immunogenetics . 28 . 1 . 53–56 . 1988 . 3132422 . 10.1007/BF00372530 . 2418453 .
• O'Sullivan DM, Larhammar D, Wilson MC, Peterson PA, Quaranta V . Structure of the human Ia-associated invariant (gamma)-chain gene: identification of 5' sequences shared with major histocompatibility complex class II genes . Proceedings of the National Academy of Sciences of the United States of America . 83 . 12 . 4484–4488 . June 1986 . 3459184 . 323758 . 10.1073/pnas.83.12.4484 . free . 1986PNAS...83.4484O .
• Koch N, Hämmerling GJ . Ia-associated invariant chain is fatty acylated before addition of sialic acid . Biochemistry . 24 . 22 . 6185–6190 . October 1985 . 3866610 . 10.1021/bi00343a023 .
• Claesson L, Peterson PA . Association of human gamma chain with class II transplantation antigens during intracellular transport . Biochemistry . 22 . 13 . 3206–3213 . June 1983 . 6576808 . 10.1021/bi00282a026 .
• Strubin M, Mach B, Long EO . The complete sequence of the mRNA for the HLA-DR-associated invariant chain reveals a polypeptide with an unusual transmembrane polarity . The EMBO Journal . 3 . 4 . 869–872 . April 1984 . 6586420 . 557440 . 10.1002/j.1460-2075.1984.tb01898.x .
• Kvist S, Wiman K, Claesson L, Peterson PA, Dobberstein B . Membrane insertion and oligomeric assembly of HLA-DR histocompatibility antigens . Cell . 29 . 1 . 61–69 . May 1982 . 6955026 . 10.1016/0092-8674(82)90090-3 . 9066996 .
• Machamer CE, Cresswell P . Biosynthesis and glycosylation of the invariant chain associated with HLA-DR antigens . Journal of Immunology . 129 . 6 . 2564–2569 . December 1982 . 10.4049/jimmunol.129.6.2564 . 6982931 . 42620266 .
• Ghosh P, Amaya M, Mellins E, Wiley DC . The structure of an intermediate in class II MHC maturation: CLIP bound to HLA-DR3 . Nature . 378 . 6556 . 457–462 . November 1995 . 7477400 . 10.1038/378457a0 . 4275956 . 1995Natur.378..457G .
• Bijlmakers MJ, Benaroch P, Ploegh HL . Mapping functional regions in the lumenal domain of the class II-associated invariant chain . The Journal of Experimental Medicine . 180 . 2 . 623–629 . August 1994 . 7519244 . 2191624 . 10.1084/jem.180.2.623 .
• Brown JH, Jardetzky TS, Gorga JC, Stern LJ, Urban RG, Strominger JL, Wiley DC . Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1 . Nature . 364 . 6432 . 33–39 . July 1993 . 8316295 . 10.1038/364033a0 . 4248668 . 1993Natur.364...33B .
• Naujokas MF, Morin M, Anderson MS, Peterson M, Miller J . The chondroitin sulfate form of invariant chain can enhance stimulation of T cell responses through interaction with CD44 . Cell . 74 . 2 . 257–268 . July 1993 . 8343954 . 10.1016/0092-8674(93)90417-O . 10295196 .
• Roche PA, Teletski CL, Stang E, Bakke O, Long EO . Cell surface HLA-DR-invariant chain complexes are targeted to endosomes by rapid internalization . Proceedings of the National Academy of Sciences of the United States of America . 90 . 18 . 8581–8585 . September 1993 . 8397411 . 47401 . 10.1073/pnas.90.18.8581 . free . 1993PNAS...90.8581R .

External links

• • Overview at Davidson College (student generated)
• School of Crystallography The Invariant Chain

Notes and References

1. Claesson L, Larhammar D, Rask L, Peterson PA . cDNA clone for the human invariant gamma chain of class II histocompatibility antigens and its implications for the protein structure . Proceedings of the National Academy of Sciences of the United States of America . 80 . 24 . 7395–7399 . December 1983 . 6324166 . 389957 . 10.1073/pnas.80.24.7395 . free . 1983PNAS...80.7395C .
2. Kudo J, Chao LY, Narni F, Saunders GF . Structure of the human gene encoding the invariant gamma-chain of class II histocompatibility antigens . Nucleic Acids Research . 13 . 24 . 8827–8841 . December 1985 . 3001652 . 318954 . 10.1093/nar/13.24.8827 .
3. Web site: UniProtKB - P04233 (HG2A_HUMAN). The UniProt Knowledgebase. The UniProt Consortium. 2020. Aug 10, 2020.
4. Cresswell P . Assembly, transport, and function of MHC class II molecules . Annual Review of Immunology . 12 . 259–293 . 1994 . 8011283 . 10.1146/annurev.iy.12.040194.001355 .
5. Farr L, Ghosh S, Moonah S . Role of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair . Frontiers in Immunology . 11 . 1273 . 2020 . 32655566 . 7325688 . 10.3389/fimmu.2020.01273 . free .
6. Book: Kuby immunology . Owen JA, Punt J, Stranford SA, Jones PP, Kuby J . 2013 . W.H. Freeman . 978-1-4641-1991-0 . 7th . New York . 820117219.
7. Schulze MS, Wucherpfennig KW . The mechanism of HLA-DM induced peptide exchange in the MHC class II antigen presentation pathway . Current Opinion in Immunology . 24 . 1 . 105–111 . February 2012 . 22138314 . 3288754 . 10.1016/j.coi.2011.11.004 .
8. Vogt AB, Kropshofer H . HLA-DM - an endosomal and lysosomal chaperone for the immune system . Trends in Biochemical Sciences . 24 . 4 . 150–154 . April 1999 . 10322421 . 10.1016/s0968-0004(99)01364-x .
9. Esposito I, Cicconi P, D'Alise AM, Brown A, Esposito M, Swadling L, Holst PJ, Bassi MR, Stornaiuolo M, Mori F, Vassilev V, Li W, Donnison T, Gentile C, Turner B, von Delft A, Del Sorbo M, Barra F, Contino AM, Abbate A, Novellino E, Thomsen AR, Christensen JP, Lahm A, Grazioli F, Ammendola V, Siani L, Colloca S, Klenerman P, Nicosia A, Dorrell L, Folgori A, Capone S, Barnes E . 6 . MHC class II invariant chain-adjuvanted viral vectored vaccines enhances T cell responses in humans . Science Translational Medicine . 12 . 548 . eaaz7715 . June 2020 . 32554708 . 7610808 . 10.1126/scitranslmed.aaz7715 . 219722045 .
10. Web site: Larkin M . Adjuvanted viral-vectored vaccine promising against hepatitis C in early trial. Reuters Health News. GI Health Foundation. June 24, 2020. Aug 10, 2020.
11. Baerlecken NT, Nothdorft S, Stummvoll GH, Sieper J, Rudwaleit M, Reuter S, Matthias T, Schmidt RE, Witte T . 6 . Autoantibodies against CD74 in spondyloarthritis . Annals of the Rheumatic Diseases . 73 . 6 . 1211–1214 . June 2014 . 23687263 . 10.1136/annrheumdis-2012-202208 . 22939188 .
12. Ghosh S, Padalia J, Ngobeni R, Abendroth J, Farr L, Shirley DA, Edwards T, Moonah S . 6 . Targeting Parasite-Produced Macrophage Migration Inhibitory Factor as an Antivirulence Strategy With Antibiotic-Antibody Combination to Reduce Tissue Damage . The Journal of Infectious Diseases . 221 . 7 . 1185–1193 . March 2020 . 31677380 . 7325720 . 10.1093/infdis/jiz579 . free .
13. Shan ZX, Lin QX, Deng CY, Tan HH, Kuang SJ, Xiao DZ, Zhu JN, Fu YH, Yu XY . 6 . [Identification of the interactions between the truncated fragments of macrophage migration inhibitory factor and CD74 using a yeast two-hybrid system] . zh . Nan Fang Yi Ke da Xue Xue Bao = Journal of Southern Medical University . 29 . 12 . 2383–6, 2390 . December 2009 . 20034881 .
14. Wang F, Shen X, Guo X, Peng Y, Liu Y, Xu S, Yang J . Spinal macrophage migration inhibitory factor contributes to the pathogenesis of inflammatory hyperalgesia in rats . Pain . 148 . 2 . 275–283 . February 2010 . 20005040 . 10.1016/j.pain.2009.11.011 . 38141283 .
15. Dobson SE, Augustijn KD, Brannigan JA, Schnick C, Janse CJ, Dodson EJ, Waters AP, Wilkinson AJ . 6 . The crystal structures of macrophage migration inhibitory factor from Plasmodium falciparum and Plasmodium berghei . Protein Science . 18 . 12 . 2578–2591 . December 2009 . 19827093 . 2798171 . 10.1002/pro.263 .
16. Piette C, Deprez M, Roger T, Noël A, Foidart JM, Munaut C . The dexamethasone-induced inhibition of proliferation, migration, and invasion in glioma cell lines is antagonized by macrophage migration inhibitory factor (MIF) and can be enhanced by specific MIF inhibitors . The Journal of Biological Chemistry . 284 . 47 . 32483–32492 . November 2009 . 19759012 . 2781663 . 10.1074/jbc.M109.014589 . free .
17. Verjans E, Noetzel E, Bektas N, Schütz AK, Lue H, Lennartz B, Hartmann A, Dahl E, Bernhagen J . 6 . Dual role of macrophage migration inhibitory factor (MIF) in human breast cancer . BMC Cancer . 9 . 230 . July 2009 . 19602265 . 2716369 . 10.1186/1471-2407-9-230 . free .
18. Farr L, Ghosh S, Moonah S . Role of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair . Frontiers in Immunology . 11 . 1273 . 2020 . 32655566 . 7325688 . 10.3389/fimmu.2020.01273 . free .
19. Jones PP, Murphy DB, Hewgill D, McDevitt HO . Detection of a common polypeptide chain in I--A and I--E sub-region immunoprecipitates . Molecular Immunology . 16 . 1 . 51–60 . January 1979 . 376435 . 10.1016/0161-5890(79)90027-0 .