CD200

For other uses, see CD200 (disambiguation).

OX-2 membrane glycoprotein, also named CD200 (Cluster of Differentiation 200) is a human protein encoded by the CD200 gene. CD200 gene is in human located on chromosome 3 in proximity to genes encoding other B7 proteins CD80/CD86. In mice CD200 gene is on chromosome 16.

CD200
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4BFI
Identifiers
Aliases	CD200, CD200 molecule, MOX1, MOX2, MRC, OX-2, CD-200
External IDs	OMIM: 155970; MGI: 1196990; HomoloGene: 4344; GeneCards: CD200; OMA:CD200 - orthologs
Gene location (Human) Chr. Chromosome 3 (human) Band 3q13.2 Start 112,332,347 bp End 112,362,812 bp
Gene location (Mouse) Chr. Chromosome 16 (mouse) Band 16 B5|16 29.53 cM Start 45,202,498 bp End 45,229,416 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in frontal pole ganglionic eminence Brodmann area 10 middle frontal gyrus hypothalamus orbitofrontal cortex Brodmann area 9 parietal pleura Brodmann area 46 Brodmann area 23 Top expressed in ascending aorta tunica media of zone of aorta ventral tegmental area dorsomedial hypothalamic nucleus ventromedial nucleus paraventricular nucleus of hypothalamus suprachiasmatic nucleus body of femur arcuate nucleus aortic valve More reference expression data BioGPS More reference expression data
Gene ontology Molecular function signaling receptor binding protein binding protein homodimerization activity cell adhesion molecule binding protein binding involved in heterotypic cell-cell adhesion glycosylated region protein binding Cellular component integral component of membrane integral component of plasma membrane membrane plasma membrane cell surface axon neuron projection soma cell body Biological process heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules cell recognition homophilic cell adhesion via plasma membrane adhesion molecules negative regulation of macrophage activation regulation of immune response negative regulation of leukocyte activation negative regulation of cell population proliferation negative regulation of NF-kappaB transcription factor activity positive regulation of CREB transcription factor activity heterotypic cell-cell adhesion positive regulation of transforming growth factor beta production cell-cell adhesion positive regulation of arginase activity positive regulation of protein-glutamine gamma-glutamyltransferase activity regulation of neuroinflammatory response negative regulation of neuroinflammatory response negative regulation of neuron death negative regulation of matrix metallopeptidase secretion negative regulation of macrophage migration negative regulation of T cell migration Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4345 17470 Ensembl ENSG00000091972 ENSMUSG00000022661 UniProt P41217 O54901 RefSeq (mRNA) NM_001004196 NM_001004197 NM_005944 NM_001318826 NM_001318828 NM_001318830 NM_001365851 NM_001365852 NM_001365853 NM_001365854 NM_001365855 NM_010818 NM_001358443 RefSeq (protein) NP_001004196 NP_001305755 NP_001305757 NP_001305759 NP_005935 NP_001352780 NP_001352781 NP_001352782 NP_001352783 NP_001352784 n/a Location (UCSC) Chr 3: 112.33 – 112.36 Mb Chr 16: 45.2 – 45.23 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

The protein encoded by this gene is a type-1 membrane glycoprotein, which contains two IgSF immunoglobulin domains, transmembrane region and a 19 amino acid long cytoplasmatic domain. CD 200 belongs to the immunoglobulin superfamily, particularly belongs to the B7 receptor family.

Expression

CD200 is expressed on dendritic cells, activated B lymphocytes, activated T lymphocytes, thymocytes, endothelial cells, neurons and osteoblast precursors. Moreover CD200 is expressed on various types of human cancer cells including hairy cell leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, malignant melanoma, multiple myeloma, testicular cancer, renal carcinoma, colon carcinoma and glioblastoma multiforme.

In innate immunity cells CD200 expression is induced upon TLRs and NLRs activation.

At the transcriptional level, CD200 expression is regulated by C/EBP-β. It was shown that CD200 expression is induced by IFN-γ and TNF-α in a NF-kappaB, STAT1 and IRF-1 dependent manner

Soluble form

Soluble CD200 (sCD200) is present in serum. It was shown that elevated levels of serum sCD200 are associated with adverse tumor prognosis in chronic lymphocytic leukemia, glioblastoma multiforme, ependymoma and medulloblastoma. Furthermore, sCD200 is associated with the expansion of myeloid-derived suppressor cells in patients with glioblastoma multiforme.

Truncated form

Truncated CD200 (CD200tr) is a truncated version of CD200 produced by alternative splicing mechanism. CD200tr lacks approximately 30 amino acids in the NH2-terminal sequence. It was shown that CD200tr acts as a competitive inhibitor to the full length CD200.

Function

CD200 interacts with its receptor CD200R and leads to immunosuppressive signaling. CD200R is strongly expressed on macrophages, neutrophils and mast cells as well as on some subtypes of B lymphocytes and T lymphocytes. In the tumor microenvironment CD200R is expressed on tumor-associated myeloid cells, particularly in tumor-associate macrophages, myeloid-derived suppressor cells, tumor-associated dendritic cells and also in regulatory T lymphocytes.

CD200-CD200R engagement inhibits T-cell immune response, shifts cytokine profile towards Th2 type response, decreases NK cell cytotoxic activity, promotes indoleamin-2,3 dioxygenase production in macrophages and triggers regulatory T cell expansion. CD200 on dendritic and lymphoid effector cells modulates the activation threshold of inflammatory response and thus contributes to the maintenance of self-tolerance. Interaction between CD200 and CD200R results in a down-regulation of basophils function and inhibits lytic function of NK cells. In IFN-γ and TNF-α producing macrophages, CD200-CD200R interaction leads to inhibition of function through Dok2 and RasGAP dependent mechanism. Elevated expression of CD200R on macrophages is associated with alternative activation of macrophages to M2 phenotype.

Mechanism of action

The engagement of CD200 to CD200R leads to tyrosine phosphorylation on CD200R cytomplasmatic PTB domain. This leads to a recruitment of adaptor proteins DOK-1 and DOK-2 that promotes binding of SHIP to DOK-1 and the recruitment of RasGAP which negatively regulates the MAPK/ERK signaling pathway. This signaling leads to the inhibition of proinflammatory cytokine release and inhibition of immune cell activation and suppression of mast cell degranulation.

Clinical significance

Pathogens modulate CD200-CD200R axis

CD200-encoding gene has been acquired by a number of viruses infecting animals as well as human, for example some human herpesviruses.

KSHV, also known as human herpesvirus-8 is, essential for the development of Kaposi sarcoma. This virus produces an ortholog of CD200, known as viral OX2 (vOX2), a 55 kDa protein. This gene is expressed on the surface of infected cells during viral replicative state. vOX-2 has an approximately 40% sequence similarity with the human gene for CD200 but shares key residues with CD200 in its binding site for CD200R. Due to its ability to engage CD200R, vOX2 can target host immune cells (T lymphocytes, macrophages, neutrophils, basophils) and inhibit anti-viral activity. Particularly, vOX2 is capable of decreasing production of TNF-α, IFN-γ from macrophages and T lymphocytes and the CD170a-dependent activation of NK cells.

Leishmania amazonensis induces expression of CD200 in the bone marrow macrophages a thus inhibits neighboring macrophages expressing CD200R that inhibits NO production during infection. Infection with Taenia crassiceps and Trypanosoma brucei brucei leads to an overexpression of CD200R on M2 macrophages and consequently to the inhibition of innate immunity response.

Rat cytomegalovirus also express CD200 ortholog known as e127 protein interacts with CD200R. e127 protein is expressed on the surface of infected cells.

In cancer

CD200 is overexpressed in cancer cells in a number of human tumors including melanoma, ovarian cancer, some B-cell malignances and small cell lung carcinoma. In the tumor microenvironment CD200 is also expressed in endothelial cells and activated T lymphocytes, B lymhocytes and myeloid cells. These cells can thus interact with cells expressing CD200R such as T regulatory cells, tumor-associated dendritic cells, tumor associated macrophages and myeloid derived suppressor cells (MDSC). It was shown that CD200 expressed on tumor cells promotes expansion of MDSCs that are capable of inhibiting anti-tumor immune response. CD200 blockade inhibits tumor growth and decreases number of MDSCs in tumor tissue.

The exact relationship between CD200 and cancer development, as well as its impact on disease prognosis, remains unclear and appears to vary depending on the type of tumor.

In transplantation

It was shown that in animal models CD200 prolongs allograft survival. This effect is associated with polarization of cytokine response towards increased production of type-2 cytokines and decreased production of type-1 cytokines. In in vitro experiments, allostimulated cells in the presence of CD200 decreased their cytotoxic function in TGF-β and IL-10 dependent mechanism.

As a drug target

Samalizumab, recombinant humanized monoclonal antibody targeting CD200 was tested in patients with chronic lymphocytic leukemia (CLL) and multiple myeloma as a phase I study. Samalizumab treatments showed a dose-dependent decrease in CD200 expression on CLL cells and decreased frequencies of circulating CD200+ CD4+ T lymphocytes in a majority of CLL patients and in multiple myeloma patients.

See also

• Cluster of differentiation

Further reading

• Gorczynski RM (2002). "Evidence for an immunoregulatory role of OX2 with its counter ligand (OX2L) in the regulation of transplant rejection, fetal loss, autoimmunity and tumor growth". Archivum Immunologiae et Therapiae Experimentalis. 49 (4): 303–309. PMID 11726033.
• Douglas J, Albertson DG, Barclay AN, Davis M, Rabbitts PH (September 1988). "RFLP and mapping of human MOX-1 gene on chromosome 3". Nucleic Acids Research. 16 (18): 9067. doi:10.1093/nar/16.18.9067. PMC 338677. PMID 2902568.
• McCaughan GW, Clark MJ, Barclay AN (1987). "Characterization of the human homolog of the rat MRC OX-2 membrane glycoprotein". Immunogenetics. 25 (5): 329–335. doi:10.1007/BF00404426. PMID 3032785. S2CID 500342.
• Wright GJ, Puklavec MJ, Willis AC, Hoek RM, Sedgwick JD, Brown MH, Barclay AN (August 2000). "Lymphoid/neuronal cell surface OX2 glycoprotein recognizes a novel receptor on macrophages implicated in the control of their function". Immunity. 13 (2): 233–242. doi:10.1016/S1074-7613(00)00023-6. PMID 10981966.
• Hoek RM, Ruuls SR, Murphy CA, Wright GJ, Goddard R, Zurawski SM, et al. (December 2000). "Down-regulation of the macrophage lineage through interaction with OX2 (CD200)". Science. 290 (5497): 1768–1771. Bibcode:2000Sci...290.1768H. doi:10.1126/science.290.5497.1768. PMID 11099416.
• Wright GJ, Jones M, Puklavec MJ, Brown MH, Barclay AN (February 2001). "The unusual distribution of the neuronal/lymphoid cell surface CD200 (OX2) glycoprotein is conserved in humans". Immunology. 102 (2): 173–179. doi:10.1046/j.1365-2567.2001.01163.x. PMC 1783166. PMID 11260322.
• Wright GJ, Cherwinski H, Foster-Cuevas M, Brooke G, Puklavec MJ, Bigler M, et al. (September 2003). "Characterization of the CD200 receptor family in mice and humans and their interactions with CD200". Journal of Immunology. 171 (6): 3034–3046. doi:10.4049/jimmunol.171.6.3034. PMID 12960329.
• Chen DX, Gorczynski RM (February 2005). "Discrete monoclonal antibodies define functionally important epitopes in the CD200 molecule responsible for immunosuppression function". Transplantation. 79 (3): 282–288. doi:10.1097/01.TP.0000149506.61000.86. PMID 15699757. S2CID 19242441.
• Chen Z, Marsden PA, Gorczynski RM (February 2006). "Cloning and characterization of the human CD200 promoter region". Molecular Immunology. 43 (6): 579–587. doi:10.1016/j.molimm.2005.04.014. hdl:1807/16344. PMID 15955564.
• Shiratori I, Yamaguchi M, Suzukawa M, Yamamoto K, Lanier LL, Saito T, Arase H (October 2005). "Down-regulation of basophil function by human CD200 and human herpesvirus-8 CD200". Journal of Immunology. 175 (7): 4441–4449. doi:10.4049/jimmunol.175.7.4441. PMID 16177086.
• Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, et al. (January 2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.
• Matsue H (December 2005). "CD 200-mediated regulation of skin immunity". The Journal of Investigative Dermatology. 125 (6): x–xi. doi:10.1111/j.0022-202X.2005.23978.x. PMID 16354172.

External links

• CD200+Antigen at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human CD200 genome location and CD200 gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: O54901 (Mouse OX-2 membrane glycoprotein (CD200)) at the PDBe-KB.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.