CCR4 | Chemokine receptors | IUPHAR Guide to IMMUNOPHARMACOLOGY

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CCR4

  Target has curated data in GtoImmuPdb

Target id: 61

Nomenclature: CCR4

Family: Chemokine receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 360 3p24 CCR4 C-C motif chemokine receptor 4 23
Mouse 7 360 9 F3 Ccr4 chemokine (C-C motif) receptor 4
Rat 7 360 8q32 Ccr4 C-C motif chemokine receptor 4
Previous and Unofficial Names
CD194 | ChemR13 | C-C chemokine receptor 4 | CC CKR4 | chemokine (C-C motif) receptor 4
Database Links
Specialist databases
GPCRDB ccr4_human (Hs), ccr4_mouse (Mm)
Other databases
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
CCL17 {Sp: Human}
CCL22 {Sp: Human} , CCL22 {Sp: Mouse}

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CCL22 {Sp: Human} Hs Full agonist 9.2 pIC50 13
pIC50 9.2 [13]
CCL17 {Sp: Human} Hs Full agonist 8.7 pIC50 13
pIC50 8.7 [13]
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
AZD1678 Mm Antagonist 9.0 pIC50 17
pIC50 9.0 (IC50 1x10-9 M) [17]
AZD1678 Rn Antagonist 9.0 pIC50 17
pIC50 9.0 (IC50 1x10-9 M) [17]
AZD1678 Hs Antagonist 8.6 pIC50 17
pIC50 8.6 (IC50 2.5x10-9 M) [17]
AZD1678 Clf Antagonist 8.5 pIC50 17
pIC50 8.5 (IC50 3.16x10-9 M) [17]
AZD2098 Mm Antagonist 8.0 pIC50 17
pIC50 8.0 (IC50 1x10-8 M) [17]
AZD2098 Rn Antagonist 8.0 pIC50 17
pIC50 8.0 (IC50 1x10-8 M) [17]
GSK2239633A Hs Antagonist 7.8 pIC50 21
pIC50 7.8 (IC50 1.48x10-8 M) [21]
Description: IC50 determined in a GTPγS binding assay using membranes from CHO cells expressing human recombinant CCR4 receptor.
AZD2098 Hs Antagonist 7.8 pIC50 17
pIC50 7.8 (IC50 1.58x10-8 M) [17]
compound 8ic [PMID: 19081254] Hs Antagonist 7.7 pIC50 29
pIC50 7.7 (IC50 1.8x10-8 M) [29]
AZD2098 Clf Antagonist 7.6 pIC50 17
pIC50 7.6 (IC50 2.51x10-8 M) [17]
compound 31 [PMID: 31259550] Hs Antagonist 7.4 pIC50 15
pIC50 7.4 (IC50 4x10-8 M) [15]
Description: Antagonism of CCL22-induced calcium flux in Chem-5 hCCR4 cells using a high-throughput FLIPR assay.
plerixafor Hs Antagonist 6.2 pIC50 10
pIC50 6.2 (IC50 6.51x10-7 M) [10]
View species-specific antagonist tables
Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Value Parameter Reference
mogamulizumab Hs Inhibition - - 1,25
[1,25]
Immunopharmacology Comments
CCR4 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation.
In disease states CCR4 is involved in recruiting T helper type 2 cell (Th2) subsets in autoimmune disorders such as asthma, allergic rhinitis, and atopic dermatitis [26], and recruiting highly immunosuppressive CD4+/CD25+/FOXP3+ regulatory T cells (Treg) cells to the tumour microenvironment [14]. As such antagonists of CCR4 are under investigation for clinical utility in inflammatory diseases and cancer. Of note is the approval of mogamulizumab, an anti-CCR4 monoclonal immuno-oncology agent, although its use can produce damaging side effects via depletion of Treg cells and their vital immune functions outwith the targeted tissues. Small molecule CCR4 antagonists have also been developed e.g. AZD1678 and AZD2098, and GSK2239633A which was advanced to Phase 1 clinical trial for asthma but not progressed further [3].
Cell Type Associations
Immuno Cell Type:  Mast cells
Immuno Cell Type:  T cells
Cell Ontology Term:   CD4-positive, CD25-positive, CCR4-positive, alpha-beta regulatory T cell (CL:0001047)
References:  14
Immuno Cell Type:  B cells
Immuno Cell Type:  B cells
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes
GO:0006954 inflammatory response TAS
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 2 GO processes
GO:0004950 chemokine receptor activity TAS
GO:0016493 C-C chemokine receptor activity IBA
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 2 GO processes
GO:0004950 chemokine receptor activity TAS
GO:0016493 C-C chemokine receptor activity IBA
Immuno Process:  Immune system development
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0002507 tolerance induction IEA
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Calcium channel
References:  20
Tissue Distribution
Th2-type lymphocytes.
Species:  Human
Technique:  RT-PCR.
References:  19
Microvascular endothelial cells.
Species:  Human
Technique:  RNase protection assay.
References:  22
Glomerular podocytes.
Species:  Human
Technique:  RT-PCR.
References:  11
Tonsil B lymphocytes.
Species:  Human
Technique:  RT-PCR.
References:  8
Blood derived mast cells.
Species:  Human
Technique:  RNase protection assay.
References:  16
Blood dendritic cells.
Species:  Human
Technique:  RT-PCR.
References:  2
Primary adult microglia and astrocytes.
Species:  Human
Technique:  Flow cytometry.
References:  9
Skin-associated and intestinal memory T cells.
Species:  Human
Technique:  Immunofluorescence.
References:  4
Platelets.
Species:  Human
Technique:  RT-PCR and flow cytometry.
References:  7
Cortical thymocytes.
Species:  Mouse
Technique:  RT-PCR.
References:  5
Hippocampal neurons.
Species:  Rat
Technique:  RT-PCR.
References:  18
Osteoblasts.
Species:  Rat
Technique:  RT-PCR.
References:  28
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Measurement of chemotaxis of blood-derived mast cells endogenously expressing the CCR4 receptor.
Species:  Human
Tissue:  Mast cells.
Response measured:  Chemotaxis.
References:  16
Measurement of Ca2+ levels in the murine pre-B cell line L1.2 transfected with the human CCR4 receptor.
Species:  Human
Tissue:  L1.2 cells.
Response measured:  Ca2+ influx.
References:  13
Measurement of chemotaxis in the murine pre-B cell line L1.2 transfected with the human CCR4 receptor.
Species:  Human
Tissue:  L1.2 cells.
Response measured:  Chemotaxis.
References:  13
Measurement of Ca2+ levels in HEK 293 cells transfected with the human CCR4 receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Ca2+ flux.
References:  27
Measurement of chemotaxis of HEK 293 cells transfected with the human CCR4 receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Chemotaxis.
References:  27
Measurement of Ca2+ currents in HEK 293 cells stably expressing N-type calcium channels and the rat CCR4 receptor, using Ba2+ as the charge carrier (IBa).
Species:  Rat
Tissue:  HEK 293 cells.
Response measured:  IBa inhibition.
References:  20
Physiological Functions
Chemotaxis.
Species:  Human
Tissue:  Mast cells.
References:  16
Chemotaxis.
Species:  Human
Tissue:  Blood CD4+CD25+ cytotoxic T lymphocyte antigen (CTLA)-4+ regulatory T cells (Treg).
References:  12
Physiological Consequences of Altering Gene Expression
CCR4 receptor knockout mice exhibit decreased mortality upon administration of high or low dose bacterial lipopolysaccharide.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  6
Following infection with A. fumigatus spores, CCR4 receptor knockout mice exhibit increased numbers of airway neutrophils and macrophages, as well as reduced numbers of peribronchial and airway eosinophils. Cholinergic stimulation induces airway hyperresponsiveness, which then subsides to a lower level in the knockout mice than wild-type. The elimination of the pathogen from the knockout mice was more rapid compared to the wild-type.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  24
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Ccr4tm1Pwr Ccr4tm1Pwr/Ccr4tm1Pwr
involves: 129P2/OlaHsd * C57BL/6
MGI:107824  MP:0008722 abnormal chemokine secretion PMID: 10811868 
Ccr4tm1Pwr Ccr4tm1Pwr/Ccr4tm1Pwr
involves: 129P2/OlaHsd * C57BL/6
MGI:107824  MP:0009333 abnormal splenocyte physiology PMID: 10811868 
Ccr4tm1Pwr Ccr4tm1Pwr/Ccr4tm1Pwr
involves: 129P2/OlaHsd * C57BL/6
MGI:107824  MP:0008658 decreased interleukin-1 beta secretion PMID: 10811868 
Ccr4tm1Pwr Ccr4tm1Pwr/Ccr4tm1Pwr
involves: 129P2/OlaHsd * C57BL/6
MGI:107824  MP:0005016 decreased lymphocyte cell number PMID: 10811868 
Ccr4tm1Pwr Ccr4tm1Pwr/Ccr4tm1Pwr
involves: 129P2/OlaHsd * C57BL/6
MGI:107824  MP:0003884 decreased macrophage cell number PMID: 10811868 
Ccr4tm1Pwr Ccr4tm1Pwr/Ccr4tm1Pwr
involves: 129P2/OlaHsd * C57BL/6
MGI:107824  MP:0008734 decreased susceptibility to endotoxin shock PMID: 10811868 
Ccr4tm1Pwr Ccr4tm1Pwr/Ccr4tm1Pwr
involves: 129P2/OlaHsd * C57BL/6
MGI:107824  MP:0008561 decreased tumor necrosis factor secretion PMID: 10811868 

References

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1. Antoniu SA. (2010) Mogamulizumab, a humanized mAb against C-C chemokine receptor 4 for the potential treatment of T-cell lymphomas and asthma. Curr. Opin. Mol. Ther., 12 (6): 770-9. [PMID:21154168]

2. Ayehunie S, Garcia-Zepeda EA, Hoxie JA, Horuk R, Kupper TS, Luster AD, Ruprecht RM. (1997) Human immunodeficiency virus-1 entry into purified blood dendritic cells through CC and CXC chemokine coreceptors. Blood, 90 (4): 1379-86. [PMID:9269754]

3. Cahn A, Hodgson S, Wilson R, Robertson J, Watson J, Beerahee M, Hughes SC, Young G, Graves R, Hall D et al.. (2013) Safety, tolerability, pharmacokinetics and pharmacodynamics of GSK2239633, a CC-chemokine receptor 4 antagonist, in healthy male subjects: results from an open-label and from a randomised study. BMC Pharmacol Toxicol, 14: 14. DOI: 10.1186/2050-6511-14-14 [PMID:23448278]

4. Campbell JJ, Haraldsen G, Pan J, Rottman J, Qin S, Ponath P, Andrew DP, Warnke R, Ruffing N, Kassam N et al.. (1999) The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells. Nature, 400 (6746): 776-80. [PMID:10466728]

5. Campbell JJ, Pan J, Butcher EC. (1999) Cutting edge: developmental switches in chemokine responses during T cell maturation. J. Immunol., 163 (5): 2353-7. [PMID:10452965]

6. Chvatchko Y, Hoogewerf AJ, Meyer A, Alouani S, Juillard P, Buser R, Conquet F, Proudfoot AE, Wells TN, Power CA. (2000) A key role for CC chemokine receptor 4 in lipopolysaccharide-induced endotoxic shock. J. Exp. Med., 191 (10): 1755-64. [PMID:10811868]

7. Clemetson KJ, Clemetson JM, Proudfoot AE, Power CA, Baggiolini M, Wells TN. (2000) Functional expression of CCR1, CCR3, CCR4, and CXCR4 chemokine receptors on human platelets. Blood, 96 (13): 4046-54. [PMID:11110672]

8. Corcione A, Tortolina G, Bonecchi R, Battilana N, Taborelli G, Malavasi F, Sozzani S, Ottonello L, Dallegri F, Pistoia V. (2002) Chemotaxis of human tonsil B lymphocytes to CC chemokine receptor (CCR) 1, CCR2 and CCR4 ligands is restricted to non-germinal center cells. Int Immunol, 14: 883-892. [PMID:12147625]

9. Flynn G, Maru S, Loughlin J, Romero IA, Male D. (2003) Regulation of chemokine receptor expression in human microglia and astrocytes. J. Neuroimmunol., 136 (1-2): 84-93. [PMID:12620646]

10. Fricker SP, Anastassov V, Cox J, Darkes MC, Grujic O, Idzan SR, Labrecque J, Lau G, Mosi RM, Nelson KL et al.. (2006) Characterization of the molecular pharmacology of AMD3100: a specific antagonist of the G-protein coupled chemokine receptor, CXCR4. Biochem. Pharmacol., 72 (5): 588-96. [PMID:16815309]

11. Huber TB, Reinhardt HC, Exner M, Burger JA, Kerjaschki D, Saleem MA, Pavenstädt H. (2002) Expression of functional CCR and CXCR chemokine receptors in podocytes. J. Immunol., 168 (12): 6244-52. [PMID:12055238]

12. Iellem A, Mariani M, Lang R, Recalde H, Panina-Bordignon P, Sinigaglia F, D'Ambrosio D. (2001) Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells. J. Exp. Med., 194 (6): 847-53. [PMID:11560999]

13. Imai T, Chantry D, Raport CJ, Wood CL, Nishimura M, Godiska R, Yoshie O, Gray PW. (1998) Macrophage-derived chemokine is a functional ligand for the CC chemokine receptor 4. J. Biol. Chem., 273 (3): 1764-8. [PMID:9430724]

14. Ishida T, Ueda R. (2006) CCR4 as a novel molecular target for immunotherapy of cancer. Cancer Sci., 97 (11): 1139-46. [PMID:16952304]

15. Jackson JJ, Ketcham JM, Younai A, Abraham B, Biannic B, Beck HP, Bui MHT, Chian D, Cutler G, Diokno R et al.. (2019) Discovery of a Potent and Selective CCR4 Antagonist That Inhibits Treg Trafficking into the Tumor Microenvironment. J. Med. Chem., 62 (13): 6190-6213. [PMID:31259550]

16. Juremalm M, Olsson N, Nilsson G. (2002) Selective CCL5/RANTES-induced mast cell migration through interactions with chemokine receptors CCR1 and CCR4. Biochem. Biophys. Res. Commun., 297 (3): 480-5. [PMID:12270118]

17. Kindon N, Andrews G, Baxter A, Cheshire D, Hemsley P, Johnson T, Liu YZ, McGinnity D, McHale M, Mete A et al.. (2017) Discovery of AZD-2098 and AZD-1678, Two Potent and Bioavailable CCR4 Receptor Antagonists. ACS Med Chem Lett, 8 (9): 981-986. [PMID:28947948]

18. Meucci O, Fatatis A, Simen AA, Bushell TJ, Gray PW, Miller RJ. (1998) Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity. Proc. Natl. Acad. Sci. U.S.A., 95 (24): 14500-5. [PMID:9826729]

19. Nanki T, Lipsky PE. (2000) Lack of correlation between chemokine receptor and T(h)1/T(h)2 cytokine expression by individual memory T cells. Int. Immunol., 12 (12): 1659-67. [PMID:11099305]

20. Oh SB, Endoh T, Simen AA, Ren D, Miller RJ. (2002) Regulation of calcium currents by chemokines and their receptors. J. Neuroimmunol., 123 (1-2): 66-75. [PMID:11880151]

21. Procopiou PA, Barrett JW, Barton NP, Begg M, Clapham D, Copley RC, Ford AJ, Graves RH, Hall DA, Hancock AP et al.. (2013) Synthesis and structure-activity relationships of indazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists. J. Med. Chem., 56 (5): 1946-60. [PMID:23409871]

22. Salcedo R, Young HA, Ponce ML, Ward JM, Kleinman HK, Murphy WJ, Oppenheim JJ. (2001) Eotaxin (CCL11) induces in vivo angiogenic responses by human CCR3+ endothelial cells. J. Immunol., 166 (12): 7571-8. [PMID:11390513]

23. Samson M, Soularue P, Vassart G, Parmentier M. (1996) The genes encoding the human CC-chemokine receptors CC-CKR1 to CC-CKR5 (CMKBR1-CMKBR5) are clustered in the p21.3-p24 region of chromosome 3. Genomics, 36: 522-526. [PMID:8884276]

24. Schuh JM, Power C, Proudfoot AE, Kunkel SL, Lukacs NW, Hogaboam CM. (2002) Airway hyperresponsiveness, but not airway remodeling, is attenuated during chronic pulmonary allergic responses to Aspergillus in CCR4-/- mice. FASEB J., 16 (10): 1313-5. [PMID:12154006]

25. Shitara K, Nakamura K, Hosaka E, Tanaka A, Koike M. (2009) Monoclonal antibodies which preferentially bind to chemokine receptors, used for immunotherapy, as antiinflammatory, aniticarcinogenic agents and for prophylaxis of respiratory system disorders or antiallergens. Patent number: US7504104. Assignee: Kyowa Hakko Kogyo Co., Ltd. Priority date: 31/08/2001. Publication date: 17/01/2010.

26. Solari R, Pease JE. (2015) Targeting chemokine receptors in disease--a case study of CCR4. Eur. J. Pharmacol., 763 (Pt B): 169-77. [PMID:25981299]

27. Wang Y, Zhang Y, Yang X, Han W, Liu Y, Xu Q, Zhao R, Di C, Song Q, Ma D. (2006) Chemokine-like factor 1 is a functional ligand for CC chemokine receptor 4 (CCR4). Life Sci., 78 (6): 614-21. [PMID:16137713]

28. Yano S, Mentaverri R, Kanuparthi D, Bandyopadhyay S, Rivera A, Brown EM, Chattopadhyay N. (2005) Functional expression of beta-chemokine receptors in osteoblasts: role of regulated upon activation, normal T cell expressed and secreted (RANTES) in osteoblasts and regulation of its secretion by osteoblasts and osteoclasts. Endocrinology, 146 (5): 2324-35. [PMID:15718270]

29. Yokoyama K, Ishikawa N, Igarashi S, Kawano N, Masuda N, Hamaguchi W, Yamasaki S, Koganemaru Y, Hattori K, Miyazaki T et al.. (2009) Potent and orally bioavailable CCR4 antagonists: Synthesis and structure-activity relationship study of 2-aminoquinazolines. Bioorg. Med. Chem., 17 (1): 64-73. [PMID:19081254]

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