Biology:CD83

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example
Dimeric CD83 extracellular domain structure

CD83 (Cluster of Differentiation 83) is a human protein encoded by the CD83 gene.[1]

Structure

The membrane-bound form of CD83 consists of an extracellular V-type immunoglobulin-like domain, a transmembrane domain and a cytoplasmic signaling tail. A free soluble form consists of the immunoglobulin-like domain alone. Membrane-bound CD83 is expected to form trimers. Soluble CD83 is able to assemble into dodecameric complexes.[2]

Gene

The CD83 gene is located on human chromosome 6p23 and mouse chromosome 13. In humans, a promoter 261 bp upstream consists of five NF-κB and three interferon regulatory factor binding sites, reflecting the involvement of CD83 in inflammation,[3] as well as binding sites for the aryl hydrocarbon receptor. The latter also occur in an enhancer sequence located 185 bp downstream, inside the second intron,[4] and may suggest negative regulation of transcription by microbial metabolites produced in the gut.

Function

The transmembrane domain of membrane-bound CD83 stabilizes MHC II, costimulatory molecules and CD28 in the membrane by antagonizing MARCH-family E3 ubiquitin ligases.[5][6]

Ligands

It is not clear what ligands interact with CD83, but membrane-bound CD83 may homotypically interact with the soluble form, suggesting autocrine immune regulation.[7] However, it contrasts with differences between the single expression of soluble CD83 on monocytes and membrane-bound CD83 on activated dendritic cells seems also as their good marker.[clarification needed][8] Soluble CD83 also binds to CD154, leading to T helper type 2 lymphocyte apoptosis by suppression of Bcl-2 inhibitors.[9]

Positive selection

The development of thymocytes during the positive-selection stage may be guided by CD83 expression on cortical thymic epithelial cells (cTECs). CD4+CD8+ double-positive thymocytes surrounded by specially differentiated cTECs called thymic nurse cells are tested for function of their αβ T cell receptor (TCR); a nonreactive TCR leads to thymocyte death by neglect. Successful rearrangement of a reactive TCR supports survival and restriction of expression to CD4 or CD8 alone on single-positive thymocytes, depending on the ability to recognize MHC II or MHC I, respectively. Upregulation of MHC II turnover on thymic nurse cells by CD83 may enlarge the population of CD4+ single-positive thymocytes.[10][6]

Regulatory T cells

CD83 KO mouse T regulatory cells revealds proinflamatory phenotype compared with WT mouse
Role of CD83 in tolerance establishment balance

T regulatory cells (Treg cells) are present in two major populations: thymically induced and peripherally induced Treg cells. All Treg cells express the Foxp3 transcription factor, establishing their suppressive phenotype. Foxp3 expression is not affected by loss of CD83 in a CD83 knockout mouse. In contrast, CD83 seems important for peripheral Treg cell induction, as suggested by reduction of this population in a conditional knockout mouse lacking CD83 specifically in Treg cells, which results in a proinflammatory phenotype.[11]

CD83 deficiency also results in an imbalances in effector function of Treg cells, as decreased expression of the T helper type 2 cell transcription factor GATA3 is also important for ST2 production.[12]

Activated Treg cells produce large amounts of soluble CD83, leading to downregulation of IRAK-1 at inflamed sites, downregulation of toll-like receptor signaling, and switching of inflammatory signals to tolerance establishment.[12]

Dendritic cells

CD83 expression is a marker for mature dendritic cells.[8] CD83 stabilizes MHC II on membrane by antagonizing MARCH E3 ubiquitin ligases. A MARCH1 knockout mouse shows accumulation of MHC II, which leads to reduced CD4+ T lymphocyte activation and reduced IL-12 production.[13] Conversely, a CD83 knockout mouse shows a reduction of MHC II and CD86, better response to bacterial infection, and higher production of IL-12 than in the wild type. CD83 seems to be an important regulator of dendritic cell phenotype and MHC II turnover, mediated by CD83-dependent endosome processing.[7]

B cells

CD83 expression correlates with rate of activation of B lymphocytes and it is under control of the B cell receptor, CD40, or Toll-like receptor activation, as in other lymphocytes, where CD83 is expressed upon stimulation. A CD83 knockout mouse shows upregulated proliferation of B lymphocytes, suggesting that CD83 acts as a brake on proliferation.[14] CD83 does not affect affinity maturation of antibodies, but its deficiency enhances immunoglobulin E class switching, suggesting that CD83 may be involved in allergy development and could be a therapeutic target for allergy treatment.[15]

See also

References

  1. ↑ "Entrez Gene: CD83 CD83 molecule". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9308. 
  2. ↑ "The human dendritic cell marker CD83 maps to chromosome 6p23". Annals of Human Genetics 63 (Pt 2): 181–3. March 1999. doi:10.1046/j.1469-1809.1999.6320181.x. PMID 10738529. 
  3. ↑ "Multiple interferon regulatory factor and NF-κB sites cooperate in mediating cell-type- and maturation-specific activation of the human CD83 promoter in dendritic cells". Molecular and Cellular Biology 33 (7): 1331–44. April 2013. doi:10.1128/MCB.01051-12. PMID 23339870. 
  4. ↑ "Quercetin induces an immunoregulatory phenotype in maturing human dendritic cells". Immunobiology 225 (4): 151929. July 2020. doi:10.1016/j.imbio.2020.151929. PMID 32115260. 
  5. ↑ Grosche, Linda; Knippertz, Ilka; König, Christina; Royzman, Dmytro; Wild, Andreas B.; Zinser, Elisabeth; Sticht, Heinrich; Muller, Yves A. et al. (17 April 2020). "The CD83 Molecule – An Important Immune Checkpoint". Frontiers in Immunology 11: 721. doi:10.3389/fimmu.2020.00721. PMID 32362900. 
  6. ↑ 6.0 6.1 von Rohrscheidt, Julia; Petrozziello, Elisabetta; Nedjic, Jelena; Federle, Christine; Krzyzak, Lena; Ploegh, Hidde L.; Ishido, Satoshi; Steinkasserer, Alexander et al. (22 August 2016). "Thymic CD4 T cell selection requires attenuation of March8-mediated MHCII turnover in cortical epithelial cells through CD83". Journal of Experimental Medicine 213 (9): 1685–1694. doi:10.1084/jem.20160316. PMID 27503071. 
  7. ↑ 7.0 7.1 Bates, J M; Flanagan, K; Mo, L; Ota, N; Ding, J; Ho, S; Liu, S; Roose-Girma, M et al. (March 2015). "Dendritic cell CD83 homotypic interactions regulate inflammation and promote mucosal homeostasis". Mucosal Immunology 8 (2): 414–428. doi:10.1038/mi.2014.79. PMID 25204675. 
  8. ↑ 8.0 8.1 Chen, Liwen; Zhu, Yibei; Zhang, Guangbo; Gao, Chao; Zhong, Weixue; Zhang, Xueguang (15 November 2011). "CD83-stimulated monocytes suppress T-cell immune responses through production of prostaglandin E2". Proceedings of the National Academy of Sciences of the United States of America 108 (46): 18778–18783. doi:10.1073/pnas.1018994108. ISSN 1091-6490. PMID 22065790. 
  9. ↑ Wu, Yong-Jin; Song, Yan-Nan; Geng, Xiao-Rui; Ma, Fei; Mo, Li-Hua; Zhang, Xiao-Wen; Liu, Da-Bo; Liu, Zhi-Gang et al. (2020). "Soluble CD83 alleviates experimental allergic rhinitis through modulating antigen-specific Th2 cell property". International Journal of Biological Sciences 16 (2): 216–227. doi:10.7150/ijbs.38722. PMID 31929750. 
  10. ↑ Kadouri, Noam; Nevo, Shir; Goldfarb, Yael; Abramson, Jakub (April 2020). "Thymic epithelial cell heterogeneity: TEC by TEC". Nature Reviews Immunology 20 (4): 239–253. doi:10.1038/s41577-019-0238-0. PMID 31804611. 
  11. ↑ Doebbeler, Marina; Koenig, Christina; Krzyzak, Lena; Seitz, Christine; Wild, Andreas; Ulas, Thomas; Baßler, Kevin; Kopelyanskiy, Dmitry et al. (7 June 2018). "CD83 expression is essential for Treg cell differentiation and stability". JCI Insight 3 (11): e99712. doi:10.1172/jci.insight.99712. PMID 29875316. 
  12. ↑ 12.0 12.1 Maitra, Urmila; Davis, Sarah; Reilly, Christopher M.; Li, Liwu (1 May 2009). "Differential Regulation of Foxp3 and IL-17 Expression in CD4 T Helper Cells by IRAK-1". The Journal of Immunology 182 (9): 5763–5769. doi:10.4049/jimmunol.0900124. PMID 19380824. 
  13. ↑ Ishido, Satoshi; Matsuki, Yohei; Goto, Eiji; Kajikawa, Mizuho; Ohmura-Hoshino, Mari (March 2010). "MARCH-I: A new regulator of dendritic cell function". Molecules and Cells 29 (3): 229–232. doi:10.1007/s10059-010-0051-x. PMID 20213309. 
  14. ↑ Kretschmer, Birte; Kühl, Svenja; Fleischer, Bernhard; Breloer, Minka (May 2011). "Activated T cells induce rapid CD83 expression on B cells by engagement of CD40". Immunology Letters 136 (2): 221–227. doi:10.1016/j.imlet.2011.01.013. PMID 21277328. 
  15. ↑ Krzyzak, Lena; Seitz, Christine; Urbat, Anne; Hutzler, Stefan; Ostalecki, Christian; Gläsner, Joachim; Hiergeist, Andreas; Gessner, André et al. (1 May 2016). "CD83 Modulates B Cell Activation and Germinal Center Responses". The Journal of Immunology 196 (9): 3581–3594. doi:10.4049/jimmunol.1502163. PMID 26983787. 

Further reading

External links



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