Alternative titles; symbols
HGNC Approved Gene Symbol: CCR6
Cytogenetic location: 6q27 Genomic coordinates (GRCh38): 6:167,111,795-167,139,141 (from NCBI)
For general information about chemokines and their receptors, see CMKBR1 (601159).
Zaballos et al. (1996) used degenerate PCR to isolate genes encoding putative chemokine receptors. One such gene, termed CKRL3 by them, encodes a 369-amino acid polypeptide with greatest similarity to the family of alpha-chemokine-binding receptors. Northern blot analysis revealed that CKRL3 is weakly expressed as a 4-kb transcript in spleen, lymph nodes, peripheral blood lymphocytes, and appendix.
Using PCR with pools of primers based on conserved sequences in chemokine receptors, Liao et al. (1997) cloned this gene and named it STRL22.
Using degenerate oligonucleotide-based reverse transcriptase PCR, Power et al. (1997) cloned cDNAs encoding human CMKBR6. Expression studies showed that CMKBR6 is the receptor for MIP-3-alpha (601960) and its activation leads to phospholipase C-dependent intracellular Ca(2+) mobilization. Similarly, Liao et al. (1997) found that MIP-3-alpha is the only chemokine that produces a calcium flux in CMKBR6-transfected cells.
Using in situ hybridization and immunohistochemistry, Homey et al. (2000) demonstrated that MIP3A, or CCL20, and its receptor, CCR6, are markedly upregulated in psoriasis (see 177900) and that CCL20-expressing keratinocytes colocalize with CLA-positive (see PSGL1; 600738) skin-infiltrating T lymphocytes in lesional psoriatic skin. By flow cytometry analysis, they showed that circulating CLA-positive memory T cells in both normal and psoriatic individuals expressed high levels of surface CCR6, which was expressed 100- to 1,000-fold higher than other chemokine receptors on this T-cell subpopulation. CCL20 was chemotactic for CLA-positive T cells at lower concentrations in psoriatic than in normal donor lymphocytes. ELISA and RT-PCR analysis showed that multiple cellular constituents of the skin produce CCL20 in response to a variety of proinflammatory mediators, including TNFA (191160)/IL1B (147720), CD40LG (300386), IFNG (147570), and IL17.
Yang et al. (1999) showed that human beta-defensins are chemotactic for immature dendritic cells and memory T cells. Human beta-defensin was selectively chemotactic for cells stably transfected to express human CCR6, a chemokine receptor preferentially expressed by immature dendritic cells and memory T cells. The beta-defensin-induced chemotaxis was sensitive to pertussis toxin and inhibited by antibodies to CCR6. The binding of iodinated LARC (CCL20; 601960), the chemokine ligand for CCR6, to CCR6-transfected cells was competitively displaced by beta-defensin. Thus, beta-defensins may promote adaptive immune responses by recruiting dendritic and T cells to the site of microbial invasion through interaction with CCR6.
Reboldi et al. (2009) found that Ccr6-deficient mice were highly resistant to induction of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS; 126200), but became susceptible after transfer of small numbers of Ccr6-positive T cells. Ccr6 was required on the first wave of Il17-producing T-helper cells (Th17 cells) entering the central nervous system (CNS) through Ccl20-expressing epithelial cells in the choroid plexus. The Ccr6-positive T cells triggered entry of a second wave of T cells that migrated in large numbers into the CNS by crossing activated parenchymal vessels. Reboldi et al. (2009) found that patients undergoing an initial demyelinating event (the first clinical episode of MS) had significantly higher frequencies of CCR6-positive/CD25 (IL2RA; 147730)-negative/CD4 (186940)-positive inflammatory T cells in cerebrospinal fluid than in peripheral blood. MS patients expressed high levels of CCL20 in inflamed tissues, in GFAP (137780)-positive astrocytes, and in choroid plexus. Reboldi et al. (2009) proposed that CCR6 and CCL20 may represent an evolutionarily conserved axis that regulates the entry and dissemination of T cells into the CNS.
Klose et al. (2013) provided evidence that the transcription factor Tbet (604895) determines the fate of a distinct lineage of CCR6-negative ROR-gamma-t (RORC; 602943)-positive innate lymphoid cells (ILCs). Postnatally emerging CCR6-ROR-gamma-t+ ILCs upregulated Tbet, and this was controlled by cues from the commensal microbiota and IL23 (605580). In contrast, CCR6+ROR-gamma-t+ ILCs, which arise earlier during ontogeny, did not express Tbet. Tbet instructed the expression of Tbet target genes such as interferon-gamma and of the natural cytotoxicity receptor NKp46 (604530). Mice genetically lacking Tbet showed normal development of CCR6-ROR-gamma-t innate lymphoid cells, but these cells could not differentiate into NKp46-expressing ROR-gamma-t+ ILCs (i.e., IL22 (605330)-producing natural killer cells) and failed to produce interferon-gamma. The production of interferon-gamma by Tbet-expressing CCR6-ROR-gamma-t+ ILCs was essential for the release of mucus-forming glycoproteins required to protect the epithelial barrier against Salmonella enterica infection. Klose et al. (2013) concluded that coexpression of Tbet and ROR-gamma-t, which is also found in subsets of IL17-producing T-helper cells, may be an evolutionarily conserved transcriptional program that originally developed as part of the innate defense against infections but that also confers an increased risk of immune-mediated pathology.
By evaluating the transcriptome in cells with increasing expression of CCR6, a marker of Th17 cell differentiation, Singh et al. (2015) detected progressive upregulation of PLZF (ZBTB16; 176797). Chromatin immunoprecipitation analysis for modified histones, p300 (EP300; 602700), and PLZF identified enhancer-like sites upstream of the transcription start site of CCR6 that bound PLZF in CCR6-positive cells. Knockdown of ZBTB16 downregulated expression of CCR6 and other Th17-associated genes. ZBTB16 and RORC cross-regulated each other, and PLZF bound to the RORC promoter in CCR6-positive cells. Singh et al. (2015) noted that Plzf was not expressed in mouse Th17 cells. They concluded that PLZF is an activator of transcription important both for Th17 differentiation and for maintenance of the Th17 phenotype in human cells.
By genomic analysis, Liao et al. (1997) determined that, unlike most chemokine receptor genes, CMKBR6 is encoded by more than 1 exon.
For discussion of association of variation in the CCR6 gene with susceptibility to rheumatoid arthritis, see 180300.
Zaballos et al. (1996) used somatic cell hybrids to map CKRL3 to human chromosome 6. Liao et al. (1997) used fluorescence in situ hybridization to map the CMKBR6 gene to chromosome 6q27.
Lukacs et al. (2001) showed that in a cockroach antigen (CA) model of allergic pulmonary inflammation, mice expressed Ccl20 within hours of challenge. Compared with these wildtype mice, Ccr6-deficient mice had reduced airway resistance, fewer eosinophils around the airway, lower levels of IL5 (147850), and reduced serum IgE in response to CA. Lukacs et al. (2001) suggested that CCL20 and CCR6 may represent novel therapeutic targets for the treatment of asthma.
Lundy et al. (2005) extended their previous findings (Lukacs et al., 2001) by showing that attenuation of airway hyperresponsiveness in Ccr6-/- mice following CA challenge was due in part to T cell defects, but also to pulmonary dendritic cell defects.
Varona et al. (2001) showed that mice with a targeted deletion in Ccr6 had normal epidermal Langerhans cells but underdeveloped Peyer patches that lacked the Cd11b (120980)/Cd11c (151510) dendritic cell subset in the subepithelial dome. The Ccr6 -/- mice also had greater numbers of T cells, particularly Cd4/Cd8 (see 186910) double-positive T cells, within the intestinal mucosa. In contact hypersensitivity studies, Ccr6 -/- mice developed more severe and more persistent inflammation. Conversely, in delayed-type hypersensitivity assays, no inflammatory response occurred. Varona et al. (2001) proposed that Ccr6-deficient mice have a defect in the activation and/or migration of the Cd4-positive T-cell subsets involved in downregulating or eliciting the inflammation response.
To investigate the role of CCR6 in the pathogenesis of chronic obstructive pulmonary disease (COPD; see 606963), Bracke et al. (2006) exposed Ccr6 -/- and wildtype mice to cigarette smoke. Bronchoalveolar lavage cell numbers increased in both wildtype and Ccr6 -/- mice after subacute and chronic cigarette smoke exposure, but the numbers of dendritic cells, activated Cd8-positive T lymphocytes, and granulocytes did not increase as much in Ccr6 -/- mice. The attenuated inflammatory response in Ccr6 -/- mice was associated with partial protection against development of pulmonary emphysema, which correlated with impaired Mmp12 (601046) production. In wildtype mice, but not Ccr6 -/- mice, cigarette smoke exposure significantly increased expression of the unique Ccr6 ligand, Ccl20, as well as Ccl2 (158105). Bracke et al. (2006) concluded that interaction of CCR6 and CCL20 contributes to the pathogenesis of cigarette smoke-induced COPD.
Bracke, K. R., D'hulst, A. I., Maes, T., Moerloose, K. B., Demedts, I. K., Lebecque, S., Joos, G. F., Brusselle, G. G. Cigarette smoke-induced pulmonary inflammation and emphysema are attenuated in CCR6-deficient mice. J. Immun. 177: 4350-4359, 2006. [PubMed: 16982869] [Full Text: https://doi.org/10.4049/jimmunol.177.7.4350]
Homey, B., Dieu-Nosjean, M.-C., Wiesenborn, A., Massacrier, C., Pin, J.-J., Oldham, E., Catron, D., Buchanan, M. E., Muller, A., de Waal Malefyt, R., Deng, G., Orozco, R., Ruzicka, T., Lehmann, P., Lebecque, S., Caux, C., Zlotnik, A. Up-regulation of macrophage inflammatory protein-3-alpha/CCL20 and CC chemokine receptor 6 in psoriasis. J. Immun. 164: 6621-6632, 2000. [PubMed: 10843722] [Full Text: https://doi.org/10.4049/jimmunol.164.12.6621]
Klose, C. S. N., Kiss, E. A., Schwierzeck, V., Ebert, K., Hoyler, T., d'Hargues, Y., Goppert, N., Croxford, A. L., Waisman, A., Tanriver, Y., Diefenbach, A. A T-bet gradient controls the fate and function of CCR6(-)ROR-gamma-t(+) innate lymphoid cells. Nature 494: 261-265, 2013. [PubMed: 23334414] [Full Text: https://doi.org/10.1038/nature11813]
Liao, F., Alderson, R., Su, J., Ullrich, S. J., Kreider, B. L., Farber, J. M. STRL22 is a receptor for the CC chemokine MIP-3alpha. Biochem. Biophys. Res. Commun. 236: 212-217, 1997. [PubMed: 9223454] [Full Text: https://doi.org/10.1006/bbrc.1997.6936]
Liao, F., Lee, H.-H., Farber, J. M. Cloning of STRL22, a new human gene encoding a G-Protein-coupled receptor related to chemokine receptors and located on chromosome 6q27. Genomics 40: 175-180, 1997. [PubMed: 9070937] [Full Text: https://doi.org/10.1006/geno.1996.4544]
Lukacs, N. W., Prosser, D. M., Wiekowski, M., Lira, S. A., Cook, D. N. Requirement for the chemokine receptor CCR6 in allergic pulmonary inflammation. J. Exp. Med. 194: 551-555, 2001. [PubMed: 11514610] [Full Text: https://doi.org/10.1084/jem.194.4.551]
Lundy, S. K., Lira, S. A., Smit, J. J., Cook, D. N., Berlin, A. A., Lukacs, N. W. Attenuation of allergen-induced responses in CCR6-/- mice is dependent upon altered pulmonary T lymphocyte activation. J. Immun. 174: 2054-2060, 2005. [PubMed: 15699135] [Full Text: https://doi.org/10.4049/jimmunol.174.4.2054]
Power, C. A., Church, D. J., Meyer, A., Alouani, S., Proudfoot, A. E. I., Clark-Lewis, I., Sozzani, S., Mantovani, A., Wells, T. N. C. Cloning and characterization of a specific receptor for the novel CC chemokine MIP-3alpha from lung dendritic cells. J. Exp. Med. 186: 825-835, 1997. [PubMed: 9294137] [Full Text: https://doi.org/10.1084/jem.186.6.825]
Reboldi, A., Coisne, C., Baumjohann, D., Benvenuto, F., Bottinelli, D., Lira, S., Uccelli, A., Lanzavecchia, A., Engelhardt, B., Sallusto, F. C-C chemokine receptor 6-regulated entry of T(H)-17 cells into the CNS through choroid plexus is required for the initiation of EAE. Nature Immun. 10: 514-523, 2009. [PubMed: 19305396] [Full Text: https://doi.org/10.1038/ni.1716]
Singh, S. P., Zhang, H. H., Tsang, H., Gardina, P. J., Myers, T. G., Nagarajan, V., Lee, C. H., Farber, J. M. PLZF regulates CCR6 and is critical for the acquisition and maintenance of the Th17 phenotype in human cells. J. Immun. 194: 4350-4361, 2015. [PubMed: 25833398] [Full Text: https://doi.org/10.4049/jimmunol.1401093]
Varona, R., Villares, R., Carramolino, L., Goya, I., Zaballos, A., Gutierrez, J., Torres, M., Martinez-A., C., Marquez, G. CCR6-deficient mice have impaired leukocyte homeostasis and altered contact hypersensitivity and delayed-type hypersensitivity responses. J. Clin. Invest. 107: R37-R45, 2001. [PubMed: 11254677] [Full Text: https://doi.org/10.1172/JCI11297]
Yang, D., Chertov, O., Bykovskala, S. N., Chen, Q., Buffo, M. J., Shogan, J., Anderson, M., Schroder, J. M., Wang, J. M., Howard, O. M. Z., Oppenheim, J. J. Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 286: 525-528, 1999. [PubMed: 10521347] [Full Text: https://doi.org/10.1126/science.286.5439.525]
Zaballos, A., Varona, R., Gutierrez, J., Lind, P., Marquez, G. Molecular cloning and RNA expression of two new human chemokine receptor-like genes. Biochem. Biophys. Res. Commun. 227: 846-853, 1996. Note: Erratum: Biochem. Biophys. Res. Commun. 231: 519 only, 1997. [PubMed: 8886020] [Full Text: https://doi.org/10.1006/bbrc.1996.1595]