CD183 CXCR3 (chemokine [C-X-C motif] receptor 3) (* See available information under CD CKR), GPR9 (G protein coupled receptor 9), CD182
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 3 glycoprotein, 7 span
Dendritic Cell
Chemokine Receptor
Plasma Cell
NK Cell
B Cell
Nonhematopoietic Cell
Eosinophil
T Cell, Activated
Hematopoietic Progenitor Cell
Heart
Kidney
Liver
Placenta
Skeletal muscle
41 / 41

Expression
CD183 is highly expressed on all types of long-term cultured T cells, including subsets marked by expression of CD4, CD8, a/b -TCR or g/d -TCR.  T cells in inflamed tissues are frequently CD183+ whereas naive T cells in peripheral blood lack this receptor, indicating that CD183 expression correlates with the effector/memory status of T cells.  Regulation of CD183 expression on T cells is similar to other chemokine receptors for inflammatory chemokines, such as CCR1, CCR2, CCR5 and reguires IL-2.  Removal of IL-2 from CD183+ T cell cultures results in rapid loss of cell surface CD183.  TCR-signaling inhibits CD183 expression and responsiveness to its ligands.  Cellular production of CD183 ligands, IP10, Mig and I-TAC, is induced by IFN-g, suggesting a prominent role of CD183 in Th1-type inflammatory processes.  Cell surface CD183 does not discriminate between Th1 and Th2 cells, however, Th2 cells respond less well to CD183 ligands than Th1 cells.  In addition to T cells, CD183 is detected by flow cytometry on minor subsets of B and activated NK cells.  Malignant B cells from chronic lymphoproliferative disorders express functional CD183 suggesting the involvement of this receptor and its ligands in B cell neoplastic diseases.  Functional expression of CD183 on non-hematopoietic cells has not been documented.  Also, CD183 is found on NK cells, plasmacytoid dendritic cells, eosinophils and GM-CSF activated CD34 (+) hematopoietic progenitors.  CD183 is also expressed on the plasma membrane. CD183 is expressed in heart, kidney, liver, skeletal muscle and placenta.

Structure
MOLECULAR FAMILY NAME: Belongs to the chemokine receptor family.

CD183 is a multi-pass type-3, 7 span 368 aa glycoprotein.  It contains an extracellular domain which contains 3 potential amino-glycosylation sites, 7 putative transmembrane-spanning domains and an intracellular cytoplasmic carboxyl-terminal domains which has 3 intracellular loop regions and contains 10 Thr/Ser residues that may become phosphorylated during CD183-mediated signaling.  The DRYLAIVHA-motif in the 2nd intracellular loop is the most highly conserved sequence element in chemokine receptors.  CD183 is a chemokine receptor which are G-proteins coupled receptors.  CD183 is shared by several receptor families.  The chemokine receptors form a division of the leukocyte chemoattractant subfamily which is part of the rhodopsin family of GPCRs. CD183 shares a 30% identity with CD181 (CXCR1) and CD182 (CXCR2).  Knockout studies in mice suggested that this receptor controls positioning of oligodendrocyte precusors in developing spinal cord arresting their migration.  
  
CD183 has a specificity for 3 chemokines, termed IP10 IFN-g  -inducible 10 kDa protein, termed Mig monokine induced by IFN-g and termed I-TAC interferon-inducible T cell a-chemoattractant.  Nomenclature for chemokines and chemokine receptors is reviewed in structural subfamily CXC chemokines, in which 1 aa residue separates the 1st 2 of 4 highly conserved Cys residues.  Historically, CD183 is the 3rd CXC chemokine receptor discovered and, therefore, commonly designated as CXCR3.  Binding of chemokines to CD183 induces cellular responses that are involved in leukocyte traffic, most notably integrin activation, cytoskeletal changes and chemotactic migration.  Inhibition by Bordetella pertussis toxin suggests the heterotrimeric G protein of the Gi-subclass couple to CD183.  Signal transduction has not been further analyzed but may include the same enzymes including phospholipases, protein kinase B and C, phosphatidylinositol-3-OH kinases, MAP kinases, G protein-coupled receptor kinases, and small GTPases that were identified in the signaling cascade induced by other chemokine receptors.  As a consequence of chemokine-induced cellular desensitization and phosphorylation-dependent receptor internalization, cellular responses are typically rapid and short in duration.  Cellular responsiveness is restored after dephosphorylation of intracellular receptors and subsequent recycling to the cell surface.

MOLECULAR MASS
Cell Type Unreduced Reduced
Activated T lymphocytes 40.6 kDa 40.6 kDa

POST-TRANSCRIPTIONAL MODIFICATION:

Alternative splicing yields 3 different isoforms.

POST-TRANSLATIONAL MODIFICATION: No information.


Ligands
CD183 associates with CXCL9, CXCL10 and CXCL11.

LIGANDS AND MOLECULES ASSOCIATED WITH CD183
Molecule Comment
IP10 IFN-g-inducible 10 kDa protein (IP10); soluble ligand
Mig monokine induced by interferon-g (Mig); soluble ligand
I-TAC interferon-inducible T cell a -chemoattractant (I-TAC); soluble ligand
G proteins heterotrimeric G proteins of the Gi subclass


Function
CD183 is a member of the CXC family of chemokine receptors CXCL-10 (IP10), CXCL9 (Mig) and CXCL11 (I-TAC).  CD183 mediates IP10 and Mig induced integrin-mediated adhesion of effector T cells to vascular endothelium.  CD183 may also play a role in augmenting Th1 cell activation and IFN-g production.  CD183 signaling induces and regulates chemotactic migration of CD183-bearing leukocytes in inflammatory-associated effector T cells.  CD183 mediates the proliferation of human mesangial cells.   CD183 mediates CXCL9 and CXCL10-induced integrin-mediated adhesion of effector T cells to vascular endothelium.  Isoform 2 is a receptor for CXCL4 and also mediates the inhibitory activities of CXCL9-11 and on the growth of human microvascular endothelial cells (HMVEC).  Isoform 2 may play a role in angiogensis and isoform 3 mediates activity of CXCL11. 

CD183 is a member of the CXC family of chemokine receptors IP10, Mig and I-TAC.  CD183 mediates IP10 and Mig induced integrin-mediated adhesion of effector T cells to vascular endothelium.  CD183 may also play a role in augmenting Th1 cell activation and IFN-g production.  CD183 signaling induces and regulates chemotactic migration of CD183-bearing leukocytes in inflammatory-associated effector T cells. 


BIOCHEMICAL ACTIVITY

CD183 is a plasma membrane receptor that induces intracellular signaling events upon ligand binding.

DISEASE RELEVANCE AND FUNCTION OF CD183 IN INTACT ANIMAL

Preferential expression of CD183 in in vitro activated cultured effector/memory T cells and the production of CD183 ligands under Th1-type inflammatory conditions strongly suggests a role of this chemokine receptor system in Th1-dependent inflammatory responses.  IP10, Mig and I-TAC are commonly produced by local cells in inflammatory lesion suggesting that CD183 and its chemokines participate in the recruitment of inflammatory cells.  CD183+ T cells were detected in inflamed tissues of patients afflicted with juvenile idiopathic/rheumatoid arthritis, multiple sclerosis, sarcoidosis and hepatitis.  CD183 is a target for the development of small molecular weight antagonists, which may be used in the treatment of diverse inflammatory diseases.  Further studies, notably in CD183-deficient mice, are needed to fully understand the importance of CD183 in the inflammatory process.  In a murine model of Toxoplasma gondii infection, neutralization of IP10 prevented recruitment and function of effector T cells.


Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD183: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD183: No information.

ADDITIONAL INSIGHTS

CD183 and its chemokine ligands, IP10, Mig and I-TAC, are expected to be essential in the T cell recruitment to sites of inflammation.  Unlike other chemokine systems, CD183 and its ligand do not participate in homeostatic, inflammation-unrelated, leukocyte traffic and are of no relevance to HIV infection.  IP10 and Mig have angiostatic activities that do not appear to involve CD183.


Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 2833P49682
MouseAF045146
Antibodies
1C6/CXCR3   View Reactivity

Revised June 25, 2008


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