OX-2 membrane glycoprotein, also named CD200 (Cluster of Differentiation 200)[5] is a humanprotein encoded by theCD200gene.[6] In humans, theCD200 gene is located on chromosome 3 in proximity to genes encoding the other B7 proteinsCD80/CD86. In mice, theCD200 gene is located onchromosome 16.[7]
The protein encoded by this gene is a type-1 membrane glycoprotein, which contains two IgSFimmunoglobulin domains, transmembrane region and a 19 amino acid long cytoplasmatic domain. CD 200 belongs to the immunoglobulin superfamily, particularly belongs to theB7 receptor family.[7][6]
CD200 is expressed on dendritic cells, activatedB lymphocytes, activatedT lymphocytes,thymocytes,endothelial cells,neurons andosteoblastprecursors. Moreover, CD200 is expressed on various types of humancancer cells includinghairy cell leukemia,acute myeloid leukemia,chronic lymphocytic leukemia,melanoma,multiple myeloma,testicular cancer,renal carcinoma, colon carcinoma andglioblastoma multiforme.[7][8]
Ininnate immunity, cellular CD200 expression is induced uponTLR andNLR activation.
At the transcriptional level, CD200 expression is regulated by C/EBP-β. It has been shown that CD200 expression is induced byIFN-γ andTNF-α in aNF-kappaB-, STAT1- and IRF-1-dependent manner.[7]
Soluble CD200 (sCD200) is present inserum. It was shown that elevated levels of serum sCD200 are associated with adversetumor prognosis in chronic lymphocytic leukemia, glioblastoma multiforme,ependymoma andmedulloblastoma. Furthermore, sCD200 is associated with the expansion of myeloid-derived suppressor cells in patients with glioblastoma multiforme.[8]
Truncated CD200 (CD200tr) is a truncated version of CD200 produced byalternative splicing mechanism. CD200tr lacks approximately 30amino acids in theNH2-terminal sequence. It was shown that CD200tr acts as a competitive inhibitor to the full length CD200.[7]
CD200 interacts with its receptorCD200R and leads to immunosuppressive signaling. CD200R is strongly expressed onmacrophages,neutrophils andmast cells as well as on some subtypes of B lymphocytes and T lymphocytes. In thetumor microenvironment CD200R is expressed on tumor-associatedmyeloid cells, particularly in tumor-associate macrophages,myeloid-derived suppressor cells, tumor-associateddendritic cells and also inregulatory T lymphocytes.[9][8]
CD200-CD200R engagement inhibits T-cell immune response, shiftscytokine profile towardsTh2 type response, decreasesNK cellcytotoxic 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 ofself-tolerance.[7][10] Interaction between CD200 and CD200R results in a down-regulation ofbasophils 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 toM2 phenotype.[7]
The engagement of CD200 to CD200R leads totyrosinephosphorylation on CD200R cytomplasmaticPTB domain. This leads to a recruitment of adaptor proteinsDOK-1 andDOK-2 that promotes binding ofSHIP to DOK-1 and the recruitment ofRasGAP which negatively regulates theMAPK/ERK signaling pathway. This signaling leads to the inhibition ofproinflammatory cytokine release and inhibition of immune cell activation and suppression ofmast cell degranulation.[8]
CD200-encoding gene has been acquired by a number ofviruses infecting animals as well as human, for example some humanherpesviruses.
KSHV, also known as human herpesvirus-8 is, essential for the development ofKaposi 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 thebone marrow macrophages a thus inhibits neighboring macrophages expressing CD200R that inhibitsNO production during infection. Infection withTaenia crassiceps andTrypanosoma brucei brucei leads to an overexpression of CD200R on M2 macrophages and consequently to the inhibition of innate immunity response.[7]
Rat cytomegalovirus also express CD200 ortholog known as e127 protein interacts with CD200R. e127 protein is expressed on the surface of infected cells.[8]
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.[7]
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.[9]
It was shown that in animal models CD200 prolongsallograft 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 inTGF-β andIL-10 dependent mechanism.[7]
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.[10]
This article incorporates text from theUnited States National Library of Medicine, which is in thepublic domain.
