CCR6

CCR6 Joshua Marion Farber* Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, NIH, 10 Center Drive, Room 11N-228, MSC 1888, Bethesda, MD 20892-1888, USA *corresponding author tel: 301-402-4910, fax: 301-402-0627, e-mail: joshua_farber@nih.gov DOI: 10.1006/rwcy.2000.22006. SUMMARY Alternative names CCR6 is a seven transmembrane domain G protei2 None currently in use. Old names include GPR-CY4, n-coupled receptor for MIP-3(cid:11), a CC chemokine ex- CKR-L3, STRL22, DCCR2, BN-1, and DRY6. pressed by a variety of cell types, including epithelial cells, in response to inflammatory stimuli. CCR6 is Structure expressed on memory T cells, B cells, and CD34+ bone marrow progenitor-derived dendritic cells. CCR6 is active on resting memory cells and can Like other chemokine receptors, CCR6 is a seven mediate both chemotaxis and adhesion of these cells transmembrane domain G protein-coupled receptor. to ICAM-1. It is presumed that CCR6 is involved in CCR6 is predicted to be 374 amino acids in length. the recruitment of memory T cells at the initiation of a response at inflammatory sites and/or in reactive Main activities and lymphoid tissue. Data also suggest that CCR6 on pathophysiological roles immature dendritic cells may be important for the recruitment ofthese cells to inflammatory sites. Since the MIP-3(cid:11) gene is also expressed in dendritic cells, CCR6 is a receptor for the chemokine LARC/MIP- CCR6 may mediate aggregation of dendritic cells, 3(cid:11)/Exodus/CK-(cid:12)4 (Baba et al., 1997; Greaves et al., memory T cells, and B cells. 1997;Liaoetal.,1997a;Poweretal.,1997),achemo- kine that, based on the expression of mRNA, is pro- duced by activated macrophages, endothelial cells, BACKGROUND and dendritic cells, and at some mucosal sites. CCR6 is expressed and functional on CD34+ bone marrow Discovery progenitor cell-derived dendritic cells (Greaves et al., 1997; Power et al., 1997; Liao et al., 1999), parti- CCR6wasdiscoveredbyseveralgroupsasanorphan cularly on ‘immature’ dendritic cells early in their receptor as part of screening for new G protein- differentiationinvitro(Dieuetal.,1998),aswellason coupled receptors or specifically for new chemokine CD4+ and CD8+ T cells (Baba et al., 1997; Greaves receptors. The first sequence entered in the database et al., 1997; Power et al., 1997; Liao et al., 1999). In was a genomic sequence, GPR-CY4, and the first the case of T cells, CCR6 is expressed exclusively on published sequences were a genomic sequence desig- those of the memory phenotype (Liao et al., 1999). natedCKR-L3(Zaballosetal.,1996)andcDNAand CCR6 is also expressed on B cells (Zaballos et al., genomic sequences for a gene designated STRL22 1996; Baba et al., 1997; Liao et al., 1997b, 1999; (Liao et al., 1997c). The protein encoded by this gene Varona et al., 1998), and MIP-3(cid:11) has been reported wasdescribedasareceptorforthechemokineLARC/ to be active on B cells from Peyer’s patches (Tanaka MIP-3(cid:11)/Exodus/CK-(cid:12)4 by several groups (Baba et al., 1999). It is presumed that CCR6 is involved et al., 1997; Liao et al., 1997a; Power et al., 1997; in the trafficking of dendritic cells and T cells, and Greaves et al., 1997) and was thereby named CCR6. perhaps B cells, particularly at mucosal sites. 2082 Joshua Marion Farber GENE PROTEIN Accession numbers Accession numbers Human gene: U45985, Z79784, U68031 Human: AAC51124 Human cDNAs: U68030, U68032 Mouse: BAA23776 Mouse gene: AJ222714 Mouse cDNA (KY411): AB009369 Sequence The human CCR6 gene is on chromosome 6q27, a site without other known chemokine receptors (Liao et al., 1997c). See Figure 2. Description of protein Sequence No information is available other than what can be See Figure 1. predicted from the primary structure. CCR6 is Figure 1 Nucleotide sequences for human and mouse CCR4. Human gene: AACTGTAGTGCATTTTGCCTTCTTTCCTTCTTAGAGTCACCTCTACTTTCCTGCTACCGCTGCCTGTGAGCTGAAGGGGCTGAACCATACACTCCTT TTTCTACAACCAGCTTGCATTTTTTCTGCCCACAATGAGCGGGGTAAGATTTTTATTTTTGGCAAGGGGTATAATTTGGGTTCACTGTGGCTACTTG AACACTACACTGCAGCTAACTCTATCTTTGTTTCCTTTCCAGGAATCAATGAATTTCAGCGATGTTTTCGACTCCAGTGAAGATTATTTTGTGTCAG TCAATACTTCATATTACTCAGTTGATTCTGAGATGTTACTGTGCTCCTTGCAGGAGGTCAGGCAGTTCTCCAGGCTATTTGTACCGATTGCCTACTC CTTGATCTGTGTCTTTGGCCTCCTGGGGAATATTCTGGTGGTGATCACCTTTGCTTTTTATAAGAAGGCCAGGTCTATGACAGACGTCTATCTCTTG AACATGGCCATTGCAGACATCCTCTTTGTTCTTACTCTCCCATTCTGGGCAGTGAGTCATGCCACTGGTGCGTGGGTTTTCAGCAATGCCACGTGCA AGTTGCTAAAAGGCATCTATGCCATCAACTTTAACTGCGGGATGCTGCTCCTGACTTGCATTAGCATGGACCGGTACATCGCCATTGTACAGGCGAC TAAGTCATTCCGGCTCCGATCCAGAACACTACCGCGCAGCAAAATCATCTGCCTTGTTGTGTGGGGGCTGTCAGTCATCATCTCCAGCTCAACTTTT GTCTTCAACCAAAAATACAACACCCAAGGCAGCGATGTCTGTGAACCCAAGTACCAGACTGTCTCGGAGCCCATCAGGTGGAAGCTGCTGATGTTGG GGCTTGAGCTACTCTTTGGTTTCTTTATCCCTTTGATGTTCATGATATTTTGTTACACGTTCATTGTCAAAACCTTGGTGCAAGCTCAGAATTCTAA AAGGCACAAAGCCATCCGTGTAATCATAGCTGTGGTGCTTGTGTTTCTGGCTTGTCAGATTCCTCATAACATGGTCCTGCTTGTGACGGCTGCAAAT TTGGGTAAAATGAACCGATCCTGCCAGAGCGAAAAGCTAATTGGCTATACGAAAACTGTCACAGAAGTCCTGGCTTTCCTGCACTGCTGCCTGAACC CTGTGCTCTACGCTTTTATTGGGCAGAAGTTCAGAAACTACTTTCTGAAGATCTTGAAGGACCTGTGGTGTGTGAGAAGGAAGTACAAGTCCTCAGG CTTCTCCTGTGCCGGGAGGTACTCAGAAAACATTTCTCGGCAGACCAGTGAGACCGCAGATAACGACAATGCGTCGTCCTTCACTATGTGATAGAAA GCTGAGTCTCCCTAAGGCATGTGTGAAACATACTCATAGATGTTATGCAAAAAAAAGTCTATGGCCAGGTATGCATGGAAAATGTGGGAATTAAGCA AAATCAAGCAAGCCTCTCTCCTGCGGGACTTAACGTGCTCATGGGCTGTGTGATCTCTTCAGGGTGGGGTGGTCTCTGATAGGTAGCATTTTCCAGC ACTTTGCAAGGAATGTTTTGTAGCTCTAGGGTATATATCCGCCTGGCATTTCACAAAACAGCCTTTGGGAAATGCTGAATTAAAGTGAATTGTTGAC AAATGTAAACATTTTCAGAAATATTCATGAAGCGGTCACAGATCACAGTGTCTTTTGGTTACAGCACAAAATGATGGCAGTGGTTTGAAAAACTAAA ACAGAAAAAAAAATGGAAGCCAACACATCACTCATTTTAGGCAAATGTTTAAACATTTTTATCTATCAGAATGTTTATTGTTGCTGGTTATAAGCAG CAGGATTGGCCGGCTAGTGTTTCCTCTCATTTCCCTTTGATACAGTCAACAAGCCTGACCCTGTAAAATGGAGGTGGAAAGACAAGCTCAAGTGTTC ACAACCTGGAAGTGCTTCGGAAAGAAGGGGACAATGGCAGAACAGGTGTTGGTGACAATTGTCACCAATTGGATAAAGCAGCTCAGGTTGTAGTGGG CCATTAGGAAACTGTCGGTTTGCTTTGATTTCCCTGGGAGCTGTTCTCTGTCGTGAGTGTCTCTTGTCTAAACGTCCATTAAGCTGAGAGTGCTATG AAGACAGGATCTAGAATAATCTTGCTCACAGCTGTGCTCTGAGTGCCTAGCGGAGTTCCAGCAAACAAAATGGACTCAAGAGAGATTTGATTAATGA ATCGTAATGAAGTTGGGGTTTATTGTACAGTTTAAAATGTTAGATGTTTTTAATTTTTTAAATAAATGGAATACTTTTTTTTTTTTTTAAAGAAAGC AACTTTACTGAGACAATGTAGAAAGAAGTTTTGTTCCGTTTCTTTAATGTGGTTGAAGAGCAATGTGTGGCTGAAGACTTTTGTTATGAGGAGCTGC AGATTAGCTAGGGGACAGCTGGAATTATGCTGGCTTCTGATAATTATTTTAAAGGGGTCTGAAATTTGTGATGGAATCAGATTTTAACAGCTCTCTT CAATGACATAGAAAGTTCATGGAACTCATGTTTTTAAAGGGCTATGTAAATATATGAACATTAGAAAAATAGCAACTTGTGTTACAAAAATACAAAC ACATGTTAGGAAGGTACTGTCATGGGCTAGGCATGGTGGCTCACACCTGTAATCCCAGCATTTTGGGAAGCTAAGATGGGTGGATCACTTGAGGTCA GGAGTTTGAGACCAGCCTGGCCAACATGGCGAAACCCCTCTCTACTAAAAATACAAAAATTTGCCAGGCGTGGTGGCGGGTGCCTGTAATCCCAGCT ACTTGGGAGGCTGAGGCAAGAGAATCGCTTGAACCCAGGAGGCAGAGGTTGCAGTGAGCCGAGATCGTGCCATTGCACTCCAGCCTGGGTGACAAAG CGAGACTCCATCTCAAAAAAAAAAAAAAAAAAAAAAGGAAAGAACTGTCATGTAAACATACCGACATGTTTAAACCTGACAATGGTGTTATTTGAAA CTTTATATTGTTCTTGTAAGCTTTAACTATATCTCTCTTTAAAATGCAAAATAATGTCTTAAGATTCAAAGTCTGTATTTTTAAAGCATGGCTTTGG CTTTGCAAAATAAAAAATGTGTTTTGTACATGAAGTAGGAATCGTATTTCAGCTTCAAGGTTCAGATTGAGGGGCCCACTGTTTGGAGAGGATGGTA TTCAGGCTTTCTCATGTCCTTCAAATCTGTTAGCGTTTGACTCTAGAAATCAAAGCAAAGGAGTGGTTACCCAGACACTTCTTTTGGTGTGATCAAT GCGCTGATGTGATCTATGAAGATGATTCATGCTTGAAAACTAGCACAGAAACATCTTGCTTATTTGCCAAAGCTGGGAGATGAGCTTCTCTGCATAA TTTAAATGTTCAGATAAATGAAGCTGACTTATTTAAGCAATAACCTTTTAAACATTTTAGCTAAGATGTATAAAAATGTTTCCAAAATATACCACAT ACTTTATTTCTTCTTAAATGTAGTACATTAGGTTACATCATTTTTCTTGCTGTCTTGGGCATCAAAACAGGTGCCATGGTAACCTGACACTCTCAGG AGACATTAAGATAGAAGGGGCTGTTCTTCAGTGGTTCCCATTGATTCTCCCCATATCTTTTTGCTCTCAGGCTCTGGCCGTCTCTTCCTGAGCCTTA ACTGTGT CCR6 2083 Figure 1 (Continued) Human cDNA: CAAACGTTCCCAAATCTTCCCAGTCGGCTTGCAGAGACTCCTTGCTCCCAGGAGATAACCAGAAGCTGCATCTTATTGACAGATGGTCATCACATTG GTGAGCTGGAGTCATCAGATTGTGGGGCCCGGAGTGAGGCTGAAGGGAGTGGATCAGAGCACTGCCTGAGAGTCACCTCTACTTTCCTGCTACCGCT GCCTGTGAGCTGAAGGGGCTGAACCATACACTCCTTTTTCTACAACCAGCTTGCATTTTTTCTGCCCACAATGAGCGGGGAATCAATGAATTTCAGC GATGTTTTCGACTCCAGTGAAGATTATTTTGTGTCAGTCAATACTTCATATTACTCAGTTGATTCTGAGATGTTACTGTGCTCCTTGCAGGAGGTCA GGCAGTTCTCCAGGCTATTTGTACCGATTGCCTACTCCTTGATCTGTGTCTTTGGCCTCCTGGGGAATATTCTGGTGGTGATCACCTTTGCTTTTTA TAAGAAGGCCAGGTCTATGACAGACGTCTATCTCTTGAACATGGCCATTGCAGACATCCTCTTTGTTCTTACTCTCCCATTCTGGGCAGTGAGTCAT GCCACTGGTGCGTGGGTTTTCAGCAATGCCACGTGCAAGTTGCTAAAAGGCATCTATGCCATCAACTTTAACTGCGGGATGCTGCTCCTGACTTGCA TTAGCATGGACCGGTACATCGCCATTGTACAGGCGACTAAGTCATTCCGGCTCCGATCCAGAACACTACCGCGCACGAAAATCATCTGCCTTGTTGT GTGGGGGCTGTCAGTCATCATCTCCAGCTCAACTTTTGTCTTCAACCAAAAATACAACACCCAAGGCAGCGATGTCTGTGAACCCAAGTACCAGACT GTCTCGGAGCCCATCAGGTGGAAGCTGCTGATGTTGGGGCTTGAGCTACTCTTTGGTTTCTTTATCCCTTTGATGTTCATGATATTTTGTTACACGT TCATTGTCAAAACCTTGGTGCAAGCTCAGAATTCTAAAAGGCACAAAGCCATCCGTGTAATCATAGCTGTGGTGCTTGTGTTTCTGGCTTGTCAGAT TCCTCATAACATGGTCCTGCTTGTGACGGCTGCAAATTTGGGTAAAATGAACCGATCCTGCCAGAGCGAAAAGCTAATTGGCTATACGAAAACTGTC ACAGAAGTCCTGGCTTTCCTGCACTGCTGCCTGAACCCTGTGCTCTACGCTTTTATTGGGCAGAAGTTCAGAAACTACTTTCTGAAGATCTTGAAGG ACCTGTGGTGTGTGAGAAGGAAGTACAAGTCCTCAGGCTTCTCCTGTGCCGGGAGGTACTCAGAAAACATTTCTCGGCAGACCAGTGAGACCGCAGA TAACGACAATGCGTCGTCCTTCACTATGTGATAGAAAGCTGAGTCTCCCTAAGGCATGTGTGAAACATACTCATAGATGTTATGCAAAAAAAAGTCT ATGGCCAGGTATGCATGGAAAATGTGGGAATTAAGCAAAATCAAGCAAGCCTCTCTCCTGCGGGACTTAACGTGCTCATGGGCTGTGTGATCTCTTC AGGGTGGGGTGGTCTCTGATAGGTAGCATTTTCCAGCACTTTGCAAGGAATGTTTTGTAGCTCTAGGGTATATATCCGCCTGGCATTTCACAAAACA GCCTTTGGGAAATGCTGAATTAAAGTGAATTGTTGACAAATGTAAACATTTTCAGAAATATTCATGAAGCGGTCACAGATCACAGTGTCTTTTGGTT ACAGCACAAAATGATGGCAGTGGTTTGAAAAACTAAAACAGAAAAAAAAATGGAAGCCAACACATCACTCATTTTAGGCAAATGTTTAAACATTTTT ATCTATCAGAATGTTTATTGTTGCTGGTTATAAGCAGCAGGATTGGCCGGCTAGTGTTTCCTCTCATTTCCCTTTGATACAGTCAACAAGCCTGACC CTGTAAAATGGAGGTGGAAAGACAAGCTCAAGTGTTCACAACCTGGAAGTGCTTCGGGAAGAAGGGGACAATGGCAGAACAGGTGTTGGTGACAATT GTCACCAATTGGATAAAGCAGCTCAGGTTGTAGTGGGCCATTAGGAAACTGTCGGTTTGCTTTGATTTCCCTGGGAGCTGTTCTCTGTCGTGAGTGT CTCTTGTCTAAACGTCCATTAAGCTGAGAGTGCTATGAAGACAGGATCTAGAATAATCTTGCTCACAGCTGTGCTCTGAGTGCCTAGCGGAGTTCCA GCAAACAAAATGGACTCAAGAGAGATTTGATTAATGAATCGTAATGAAGTTGGGGTTTATTGTACAGTTTAAAATGTTAGATGTTTTTAATTTTTTA AATAAATGGAATACTTTTTTTTTTTTTAAAGAAAGCAACTTTACTGAGACAATGTAGAAAGAAGTTTTGTTCCGTTTCTTTAATGTGGTTGAAGAGC AATGTGTGGCTGAAGACTTTTGTTATGAGGAGCTGCAGATTAGCTAGGGGACAGCTGGAATTATGCTGGCTTCTGATAATTATTTTAAAGGGGTCTG AAATTTGTGATGGAATCAGATTTTAACAGCTCTCTTCAATGACATAGAAAGTTCATGGAACTCATGTTTTTAAAGGGCTATGTAAATATATGAACAT TAGAAAAATAGCAACTTGTGTTACAAAAATACAAACACATGTTAGGAAGGTACTGTCATGGGCTAGGCATGGTGGCTCACACCTGTAATCCCAGCAT TTTGGGAAGCTAAGATGGGTGGATCACTTGAGGTCAGGAGTTTGAGACCAGCCTGGCCAACATGGCGAAACCCCTCTCTACTAAAAATACAAAAATT TGCCAGGCGTGGTGGCGGGTGCCTGTAATCCCAGCTACTTGGGAGGCTGAGGCAAGAGAATCGCTTGAACCCAGGAGGCAGAGGTTGCAGTGAGCCG AGATCGTGCCATTGCACTCCAGCCTGGGTGACAGAGCGAGACTCCATCTCAAAAAAAAAAAAAAAAAA Mouse gene: TCTGCTCTCCCAACATCTGCACTAGTGAGAGTGTGGTTGAACTGCCCACTTCCCTTTCTACACCAGATCTGGCTCTCCCATCCACATAGAGAACCAC GCCTGCCTGGGGTGAGAATCTACTTTATCTTGGCAGGGACTCTGGCATGGCTAGGTGTGGTTGCTTGAAATCACACTGTCACGATTTCTATTTTCAT TATCATTCAGGAATGAATTCCACAGAGTCCTACTTTGGAACGGATGATTATGACAACACAGAGTATTATTCTATTCCTCCAGACCATGGGCCATGCT CCCTAGAAGAGGTCAGAAACTTCACCAAGGTATTTGTGCCAATTGCCTACTCCTTAATATGTGTCTTTGGCCTCCTGGGCAACATTATGGTGGTGAT GACCTTTGCCTTCTACAAGAAAGCCAGATCCATGACTGACGTCTACCTGTTGAACATGGCCATCACAGACATACTCTTTGTCCTCACCCTACCGTTC TGGGCAGTTACTCATGCCACCAACACTTGGGTTTTCAGCGATGCACTGTGTAAACTGATGAAAGGCACATATGCGGTCAACTTTAACTGTGGGATGC TGCTCCTGGCCTGTATCAGCATGGACCGGTACATTGCCATCGTCCAGGCAACCAAATCTTTCCGGGTACGCTCCAGAACACTGACGCACAGTAAGGT CATCTGTGTGGCAGTGTGGTTCATCTCCATCATCATCTCAAGCCCTACATTTATCTTCAACAAGAAATACGAGCTGCAGGATCGTGATGTCTGTGAG CCACGGTACAGGTCTGTCTCAGAGCCCATCACGTGGAAGCTGCTGGGTATGGGACTGGAGCTGTTCTTTGGGTTCTTCACCCCTTTGCTGTTTATGG TGTTCTGCTATCTGTTCATTATCAAGACCTTGGTGCAGGCCCAGAACTCCAAGAGGCACAGAGCCATCCGAGTCGTGATCGCTGTGGTTCTCGTGTT CCTGGCTTGTCAGATCCCTCACAACATGGTCCTCCTCGTGACTGCGGTCAACACGGGCAAAGTGGGCCGGAGCTGCAGCACCGAGAAAGTCCTCGCC TACACCAGGAACGTGGCCGAGGTCCTGGCTTTCCTGCATTGCTGCCTCAACCCCGTGTTGTATGCGTTTATTGGACAGAAATTCAGAAACTACTTCA TGAAGATCATGAAGGATGTGTGGTGTATGAGAAGGAAGAATAAGATGCCTGGCTTCCTCTGTGCCCGGGTTTACTCGGAAAGCTACATCTCCAGGCA GACCAGTGAGACCGTCGAAAATGATAATGCATCGTCCTTTACCATGTAACACGAGAGCACAAAGCAACATTGCCCCAAAAGCCTTGGTGAAACTTGC TATTACATATGAAAAAAAAAAAAAGCCATGCCCAAATATGTACAGTAACTATGGAAATTCAGCAAAGACTTCCTGCAAGTTCAGAAACAGCCATGAG GTGGCACTATCAGCCAAATTCTTCCAGGTTGTTGGTTGACAAGAAACATTGCAGCTCCTCCCAGGTTTGGTTCTACAAAATAAGATGGGAAATGCCC AGATTACTGGGTTTAGTTGCTTAATGAACATAAACATATTCCAGAAACGTTTCATGAAGGGGTTCACAGAACTAGTTGACCCCCTAACACCCCATAG CCACAAAACAAGGATGTTACCTTGA Mouse cDNA: GGCTGCGAGAAGACGACAGAAGGGGGAGCACTGCTGGTTGTGTCTGTCAACAGAATAGTCCTCACATTCTTAGGACTGGAGCCTGGATAACCACTGA GGCAGGAGTACCTGGCCAGTCTACTTTGGAGCTCAGCATTTTCTGGGGAATGAATTCCACAGAGTCCTACTTTGGAACGGATGATTATGACAACACA GAGTATTATTCTATTCCTCCAGACCATGGGCCATGCTCCCTAGAAGAGGTCAGAAACTTCACCAAGGTATTTGTGCCAATTGCCTACTCCTTAATAT GTGTCTTTGGCCTCCTGGGCAACATTATGGTGGTGATGACCTTTGCCTTCTACAAGAAAGCCAGATCCATGACTGACGTCTACCTGTTGAACATGGC CATCACAGACATACTCTTTGTCCTCACCCTACCGTTCTGGGCAGTTACTCATGCCACCAACACTTGGGTTTTCAGCGATGCACTGTGTAAACTGATG AAAGGCACATATGCGGTCAACTTTAACTGTGGGATGCTGCTCCTGGCCTGTATCAGCATGGACCGGTACATTGCCATCGTCCAGGCAACCAAATCTT TCCGGGTACGCTCCAGAACACTGACGCACAGTAAGGTCATCTGTGTGGCAGTGTGGTTCATCTCCATCATCATCTCAAGCCCTACATTTATCTTCAA CAAGAAATACGAGCTGCAGGATCGTGATGTCTGTGAGCCACGGTACAGGTCTGTCTCAGAGCCCATCACGTGGAAGCTGCTGGGTATGGGACTGGAG CTGTTCTTTGGGTTCTTCACCCCTTTGCTGTTTATGGTGTTCTGCTATCTGTTCATTATCAAGACCTTGGTGCAGGCCCAGAACTCCAAGAGGCACA GAGCCATCCGAGTCGTGATCGCTGTGGTTCTCGTGTTCCTGGCTTGTCAGATCCCTCACAACATGGTCCTCCTCGTGACTGCGGTCAACACGGGCAA AGTGGGCCGGAGCTGCAGCACCGAGAAAGTCCTCGCCTACACCAGGAACGTGGCCGAGGTCCTGGCTTTCCTGCATTGCTGCCTCAACCCCGTGTTG TATGCGTTTATTGGACAGAAATTCAGAAACTACTTCATGAAGATCATGAAGGATGTGTGGTGTATGAGAAGGAAGAATAAGATGCCTGGCTTCCTCT GTGCCCGGGTTTACTCGGAAAGCTACATCTCCAGGCAGACCAGTGAGACCGTCGAAAATGATAATGCATCGTCCTTTACCATGTAACACGAGAGCAC AAAGCAACATTGCCCCAAAAGCCTTGGTGAAACTTGCTATT 2084 Joshua Marion Farber Figure2 ComparisonbetweenhumanandmouseCCR6aminoacidsequences.Numbersattherightindicate the positions of the residues at the end of each line. Solid backgrounds indicate identities between the two proteins. Dots mark gaps introduced to create an optimal alignment. Tildes mark positions without corresponding residues. Putative transmembranedomains are indicated. The alignmentwas created using the PileUp and PrettyBox programs of the Wisconsin Sequence Analysis Package, Genetics Computer Group, Madison, WI. predicted to contain 374 amino acids, with features Cell types and tissues expressing that are typical for a member of the chemokine the receptor receptor subfamily of the seven transmembrane domain G protein-coupled receptor superfamily. These include an acidic N-terminal domain, a small CCR6 mRNA is expressed in lymphoid tissue and basic third intracellular loop, cysteine residues in including spleen, lymph node, thymus, appendix,and the N-terminal domain (C36) and the third extra- peripheral blood lymphocytes (Zaballos et al., 1996; cellular loop (C288), and a conserved DRY motif Liao et al., 1997c; Varona et al., 1998) and mRNA following the third transmembrane domain. and protein are found in/on CD4+CD8+ T cells, dendritic cells derived from CD34+ bone marrow progenitors, and B cells (Zaballos et al., 1996; Baba et al., 1997; Greaves et al., 1997; Liao et al., 1997b, Relevant homologies and 1999; Power et al., 1997; Varona et al., 1998). On species differences T cells, CCR6 is limited to those with a memory phenotype(Liaoetal.,1999).CCR6isfoundnotonly Whileobviouslyrelatedtootherchemokinereceptors on freshly isolated peripheral blood T cells, but also by sequence, CCR6 is not closely related to other on tumor-infiltrating lymphocytes that have been receptors, showing greatest similarity to CCR7 (39% repeatedly activated in vitro (Liao et al., 1997a,b,c). identity).Overall,humanCCR6isidenticalat74%of its residues, as compared with mouse protein. As Regulation of receptor expression shown in Figure 2, mismatched residues are found disproportionately in the N-terminal region. Some investigators have reported induction of CCR6 mRNA on T cells after treatment with IL-2 (Baba et al., 1997), although others have reported down- Affinity for ligand(s) regulationofmRNAafterTcellactivationwithanti- CD3 and PMA (Greaves et al., 1997). Activation of K for MIP-3(cid:11) on CCR6-transfected cells is 0.1– Tcells in vitrowithanti-CD3orIL-2 didnotupregu- d 12nM (Baba et al., 1997; Greaves et al., 1997; Power late CCR6 surface expression (Liao et al., 1999) or et al., 1997) and on lymphocytes is 0.4nM (Hieshima responses to LARC/MIP-3(cid:11). Maturation of CD34+ et al., 1997). progenitor-derived dendritic cells in vitro was CCR6 2085 associatedwithdownregulationofCCR6mRNAand Dieu, M. C., Vanbervliet, B., Vicari, A., Bridon, J. M., responses to LARC/MIP-3(cid:11) (Dieu et al., 1998). Oldham, E., Ait-Yahia, S., Briere, F., Zlotnik, A., Lebecque, S., and Caux, C. (1998). Selective recruitment of immature and mature dendritic cells by distinct chemokines SIGNAL TRANSDUCTION expressedindifferentanatomicsites.J.Exp.Med.188,373–386. Greaves, D. R., Wang, W., Dairaghi, D. J., Dieu, M. C., Saint- Vis,B.,Franz-Bacon,K.,Rossi,D.,Caux,C.,McClanahan,T., Cytoplasmic signaling cascades Gordon,S.,Zlotnik,A.,andSchall,T.J.(1997).CCR6,aCC chemokine receptor that interacts with macrophage inflamma- toryprotein3alphaandishighlyexpressedinhumandendritic Calcium signaling was blocked or diminished in cells.J.Exp.Med.186,837–844. tumor-infiltrating lymphocytes and in transfected Hieshima, K., Imai, T., Opdenakker, G., Van Damme, J., cells by the addition of pertussis toxin, implicating Kusuda, J., Tei, H., Sakaki, Y., Takatsuki, K., Miura, R., G(cid:11) proteins (Liao et al., 1997a; Power et al., 1997), Yoshie, O., and Nomiyama, H. (1997). Molecular cloning of i a novel human CC chemokine liver and activation-regulated andintransfectedcellsbyinhibitingphospholipaseC chemokine (LARC) expressed in liver. Chemotactic activity and depleting stores of intracellular calcium (Power for lymphocytes and gene localization on chromosome 2. et al., 1997). J.Biol.Chem.272,5846–5853. Liao, F., Alderson, R., Su, J., Ullrich, S. J., Kreider, B. L., and Farber, J. M. (1997a). STRL22 is a receptor for the CC BIOLOGICAL CONSEQUENCES chemokineMIP-3alpha.Biochem.Biophys.Res.Commun.236, 212–217. OF ACTIVATING OR INHIBITING Liao,F.,Alkhatib,G.,Peden,K.W.C.,Sharma,G.,Berger,E.A., RECEPTOR AND andFarber,J.M.(1997b).STRL33,anovelchemokinerecep- tor-likeprotein,functionsasafusioncofactorforbothmacro- PATHOPHYSIOLOGY phage-tropic and T cell line-tropic HIV-1. J. Exp. Med. 185, 2015–2023. Unique biological effects of Liao, F., Lee, H.-H., and Farber, J. M. (1997c). Cloning of STRL22, a new human gene encoding a G protein-coupled activating the receptors receptorrelatedtochemokinereceptorsandlocatedonchromo- some6q27.Genomics40,175–180. Liao,F.,Rabin,R.L.,Smith,C.S.,Sharma,G.,Nutman,T.B., CCR6 is unusual in that it is a receptor for an and Farber, J. M. (1999). CC-chemokine receptor 6 is inflammation-induced chemokine that functions well expressedondiversememorysubsetsofTcellsanddetermines on freshly isolated lymphocytes, i.e. on nonactivated responsiveness to macrophage inflammatory protein 3 alpha. J.Immunol.162,186–194. cells, producing chemotaxis (Hieshima et al., 1997), Power, C. A., Church, D. J., Meyer, A., Alouani, S., calciumflux(Liaoetal.,1997a),andrapidadherence Proudfoot, A. E. I., Clark-Lewis, I., Sozzani, S., to ICAM-1-coated glass under conditions of flow Mantovani,A.,andWells,T.N.C.(1997).Cloningandchar- (Campbelletal.,1998).Theseactivitieswerefoundon acterization of a specific receptor for the novel CC both CD4+ and CD8+ T cells, and were limited to chemokine MIP-3(cid:11) from lung dendritic cells. J. Exp. Med. 186,825–835. T cells with a memory phenotype (Campbell et al., Tanaka, Y., Imai, T., Baba, M., Ishikawa, I., Uehira, M., 1998; Liao et al., 1999). Consequently, CCR6 is the Nomiyama, H., and Yoshie, O. (1999). Selective expression of only chemokine receptor that functions well in the liver and activation-regulated chemokine (LARC) in intes- above assays specifically on nonactivated memory tinal epithelium in mice and humans. Eur. J. Immunol. 29, T cells. CCR6 is also unusual in being expressed and 633–642. Varona, R., Zaballos, A., Gutierrez, J., Martin, P., Roncal, F., functionalonasubsetofimmaturedendriticcellsand Albar, J. P., Ardavin, C., and Marquez, G. (1998). Molecular then being downregulated as the dendritic cells cloning,functionalcharacterizationandmRNAexpressionana- mature (Dieu et al., 1998). lysis of the murine chemokine receptor CCR6 and its specific ligandMIP-3alpha.FEBSLett.440,188–194. Zaballos,A.,Varona,R.,Gutierrez,J.,Lind,P.,andMarquez,G. References (1996). Molecular cloning and RNA expression of two new human chemokine receptor-like genes Biochem. Biophys. Res. Commun.227,846–853. Baba, M., Imai, T., Nishimura, M., Kakizaki, M., Takagi, S., Hieshima, K., Nomiyama, H., and Yoshie, O. (1997). Identification of CCR6, the specific receptor for a novel lymphocyte-directed CC chemokine LARC. J. Biol. Chem. LICENSED PRODUCTS 272,14893–14898. Campbell, J. J., Hedrick, J., Zlotnik, A., Siani, M. A., Thompson, D. A., and Butcher, E. C. (1998). Chemokines Anti-human CCR6 mouse IgG monoclonal anti- 2B and the arrest of lymphocytes rolling under flow conditions. body, clone 53103.111 from R&D Systems for flow Science279,381–384. cytometry.