Chemokine CCL27 (CTACK/ALP/ILC) (GPR-2, CCR10)

Cutting Edge: The Orphan Chemokine Receptor G Protein-Coupled Receptor-2 (GPR-2, CCR10) Binds the Skin-Associated Chemokine CCL27 (CTACK/ALP/ILC) This information is current as of September 26, 2021. Bernhard Homey, Wei Wang, Hortensia Soto, Matthew E. Buchanan, Andrea Wiesenborn, Daniel Catron, Anja Müller, Terrill K. McClanahan, Marie-Caroline Dieu-Nosjean, Rocio Orozco, Thomas Ruzicka, Percy Lehmann, Elizabeth Oldham and Albert Zlotnik Downloaded from J Immunol 2000; 164:3465-3470; ; doi: 10.4049/jimmunol.164.7.3465 http://www.jimmunol.org/content/164/7/3465 http://www.jimmunol.org/

References This article cites 17 articles, 10 of which you can access for free at: http://www.jimmunol.org/content/164/7/3465.full#ref-list-1

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Cutting Edge: The Orphan Chemokine Receptor G Protein-Coupled Receptor-2 (GPR-2, CCR10) Binds the Skin- Associated Chemokine CCL27 (CTACK/ALP/ILC)1

Bernhard Homey,2* Wei Wang,2* Hortensia Soto,* Matthew E. Buchanan,* Andrea Wiesenborn,† Daniel Catron,* Anja Mu¨ller,*

Terrill K. McClanahan,* Downloaded from Marie-Caroline Dieu-Nosjean,‡ Rocio Orozco,§ Thomas Ruzicka,† Percy Lehmann,† Elizabeth Oldham,* and Albert Zlotnik3* http://www.jimmunol.org/

in cDNA libraries derived from normal or lesional psoriatic skin We recently reported the identification of a chemokine (3–6). These observations suggested both a homeostatic role for (CTACK), which has been renamed CCL27 according to a new CTACK as well as a role during inflammatory and autoimmune systematic chemokine nomenclature. We report that CCL27 skin diseases. We also observed that CCL27 preferentially attracts binds the previously orphan chemokine receptor GPR-2, as a subpopulation of skin-homing CLAϩ (cutaneous lymphocyte detected by calcium flux and chemotactic responses of GPR-2 Ag) (7) memory T cells in vitro (4). However, many questions transfectants. We renamed this receptor CCR10. Because of remain to be explored on the role of this chemokine in both normal the skin-associated expression pattern of CCL27, we focused and pathological skin conditions. One of the most critical aspects by guest on September 26, 2021 on the expression of CCL27 and CCR10 in normal skin com- was to find its receptor. pared with inflammatory and autoimmune skin diseases. Here, we report that the previously orphan G protein-coupled CCL27 is constitutively produced by keratinocytes but can receptor-2 (GPR-2)4 binds CCL27. Furthermore, we explored the also be induced upon stimulation with TNF-␣ and IL-1␤. expression pattern of this ligand/receptor pair in normal and in- CCR10 is not expressed by keratinocytes and is instead ex- flamed skin. Our results suggest both a homeostatic and an inflam- pressed by melanocytes, dermal fibroblasts, and dermal mi- matory role for CCL27/CCR10 in the skin. crovascular endothelial cells. CCR10 was also detected in T cells as well as in skin-derived Langerhans cells. Taken together, these observations suggest a role for this novel ligand/ Materials and Methods receptor pair in both skin homeostasis as well as a potential Cloning of full-length CCR10 (GPR-2) and creation of stable role in inflammatory responses. The Journal of Immunology, cell lines 2000, 164: 3465–3470. Full-length human CCR10 (GPR-2) was cloned from a cDNA library generated from a human B cell EBV-positive tumor cell line (B103) using a 1064-bp probe amplified from human genomic DNA. This fragment was he chemokines are small secreted molecules that regulate generated by PCR using the partial sequence of CCR10 (GPR-2) as re- hemopoietic cell trafficking in the body (1, 2). The reported by Marchese et al. (8). The sequence of full-length human GPR-2 cently reported chemokine, CCL27/CTACK/Eskine/ILC/ has been deposited in GenBank under accession number AF208237. To T generate stable transfectants, full-length expression constructs were made ALP, is constitutively produced by keratinocytes and is present in BAF/3 cells. Human CCR10 (GPR-2) was cloned into the retroviral

*DNAX Research Institute, Palo Alto, CA 94304; †Department of Dermatology, Uni- versity of Du¨sseldorf, Du¨sseldorf, Germany; ‡Schering Plough, Laboratory for Im- 1 DNAX Research Institute is supported by Schering-Plough Corporation. munological Research, Dardilly, France; and §Instituto Nacional de la Nutricio´n Sal- vador Zubira´n, Me´xico City, Me´xico 2 B.H. and W.W. contributed equally to this paper. Received for publication December 23, 1999. Accepted for publication February 3 Address correspondence and reprint requests to Dr. Albert Zlotnik, Department of 2, 2000. Immunobiology, DNAX Research Institute, 901 California Avenue, Palo Alto, CA 94303-1104. E-mail address: [email protected] The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance 4 Abbreviations used in this paper: GPR, G protein-coupled receptor; LC, Langerhans with 18 U.S.C. Section 1734 solely to indicate this fact. cell.

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FIGURE 1. Amino acid sequence alignment of human CCR10. Amino acid sequences of the original and full-length hGPR-2 are aligned with other chemokine receptors, hCCR8, hCCR9, hCXCR1, and hCXCR2. Dark-shaded boxes indicate identical amino acids. Conserved amino acids are shaded light ءء ء grey. , The missing amino acid sequence at the NH2 terminus of the full-length in comparison to the previously published truncated form of hGPR-2. , http://www.jimmunol.org/ The characteristic DRY box motif.

vector, pMX-CD8-myc. Transfectants underwent selection in G418 and dermatitis (n ϭ 10), or cutaneous lupus erythematosus (n ϭ 10), or from were further enriched by FACS-sorting using an anti-myc Ab (PharMingen, normal (n ϭ 10) healthy individuals. Skin samples were immediately fro- San Diego). zen in liquid nitrogen and stored at Ϫ80°C. This study was approved by local ethics committees. Calcium mobilization assays Real-time quantitative PCR (TaqMan) analysis of CCL27 and by guest on September 26, 2021 To identify the CCL27 receptor, we tested a panel of known human CCR10 mRNA expression (CCR1, 2, 3, 4, 5, 6, 7, 8, 9; XCR1; CX3CR; CXCR1, 2, 3, 4, 5) chemokine and orphan (STRL33, GPR-15, GPR-2) GPCR transfectants for signaling RNA from both homogenized skin samples or human cells was extracted using a calcium mobilization assay as described previously (9). Mouse using RNA STAT 60 according to the manufacturer’s protocol (Tel-Test, CCL27 was obtained from R&D Systems (Minneapolis, MN), and human Friedensburg, TX). Four micrograms of RNA were treated with DNase I CCL27 was chemically synthesized by Gryphon Sciences (South San (Boehringer Mannheim, Mannheim, Germany) and reverse transcribed Francisco, CA). with oligo dT14–18 (Life Technologies, Gaithersburg, MD) and random hexamer primers (Promega, Madison, WI) using standard protocols. cDNA Transwell chemotaxis assay was diluted to a final concentration of 10 ng/␮l. cDNA was analyzed for the expression of human CCL27 and CCR10 (GPR-2) genes by the flu- 6 The transwell chemotaxis assays were performed using 10 BAF/3- orogenic 5Ј-nuclease PCR assay (13) using a Perkin-Elmer ABI Prism hCCR10(GPR-2) transfectant or parental cells as previously described (4). 7700 Sequence Detection System (Perkin-Elmer, Foster City, CA). Briefly, 10 ␮l cDNA (100 ng) were amplified in the presence of 12.5 ␮l TaqMan Cell isolation and cell culture universal master mix (Perkin-Elmer), 0.625 ␮l gene-specific TaqMan probe, 0.5 ␮l gene-specific forward and reverse primers, and 0.5 ␮l water. Human primary epidermal keratinocytes, dermal fibroblasts, melanocytes, As an internal positive control, 0.125 ␮l 18S RNA-specific TaqMan probe and dermal microvascular endothelial cells were purchased from Clonetics and 0.125 ␮l 18S RNA-specific forward and reverse primers were added to (San Diego, CA) and cultured in keratinocyte, fibroblast, melanocyte, or each reaction. Specific primers and probes for CCL27, CCR10, and the endothelial cell growth medium (Clonetics, San Diego, CA). Cells were ␣ ␤ ␥ other chemokine receptors measured were obtained from Perkin-Elmer. treated with TNF- (10 ng/ml)/IL-1 (5 ng/ml), IFN- (20 ng/ml), IL-4 Samples underwent the following stages: stage 1, 50°C for 2 min; stage 2, (50 ng/ml), IL-10 (100 ng/ml) (R&D Systems), or left untreated. The epi- ␥␦ 95°C for 10 min; and stage 3, 95°C for 15 s followed by 60°C for 1 min. dermal T cell line, 7-17, was kindly provided by Richard Boismenu Stage 3 was repeated 40 times. Gene-specific PCR products were measured (The Scripps Institute, La Jolla, CA) and cultured as described (10). ␥␦ ␣ by means of an ABI PRISM 7700 Sequence Detection System (Perkin- Epidermal T cells were left untreated or stimulated with Con A, TNF- Elmer) continuously during 40 cycles. Standard curves for CCL27 and (10 ng/ml)/IL-1␤ (5 ng/ml), for 6 or 18 h. Generation of dendritic cells ϩ CCR10 expression were generated amplifying 10-fold serial dilutions of either from cord blood CD34 hemopoietic progenitor cells or from pe- known quantities of CCL27 and CCR10 plasmid DNA. Quantification of ripheral blood monocytes was performed as described (11). Human skin- target gene expression was obtained using sequence detector system soft- derived Langerhans cells (LC) were isolated form normal skin of patients ware (Perkin-Elmer). Human cDNA libraries used in this study were gen- undergoing plastic surgery (12). Enrichment of LC was achieved as de- erated as described previously (1, 4, 14, 15). For analyses using cDNA scribed (12). PBMCs were isolated using standard techniques, and T cell libraries, a human GAPDH-specific primer/probe pair was used as internal enrichment was performed using T cell enrichment columns (R&D positive control. Systems).

Biopsy samples Results Six-millimeter punch biopsies were taken, after obtaining informed con- We have previously described the discovery and characterization sent, from either lesional skin of patients with psoriasis (n ϭ 21), atopic of a new CC chemokine (CTACK) now designated CCL27. This The Journal of Immunology 3467

of CCL27 to any of the known chemokine receptors, suggesting that it had a speciﬁc new receptor. However, there are several orphan “chemokine-like” receptors, including STRL33 (16) and GPR-15 (17) as well as GPR-2 (8). All of these are very likely to be chemokine receptors because they share a high degree of ho- mology with known chemokine receptors, and they exhibit a characteristic DRY motif, found in other chemokine receptors. We tested CCL27 for binding to transfectants of these receptors. Ini- tially, we tested the published GPR-2 sequence, although it was

missing part of the NH2 terminus. Transfectants of this molecule failed to show a calcium ﬂux when tested against a panel of 35 human chemokines. We then sought to obtain a full-length clone encoding this receptor. Fig. 1 shows the sequence of a clone of human GPR-2, which was established from a cDNA library prepared from the 103 human B cell line. Comparison with the original published sequence (8) indicates that the ﬁrst 8 aa were miss-

ing from the NH2 terminus of the original sequence (Fig. 1). BAF/3 transfectants of the full-length clone were tested against

a panel of human chemokines using a calcium flux assay. Fig. 2, Downloaded from A and C show that both human and mouse CCL27 induced a specific calcium flux in the transfectants but not the parental BAF/3 cells, indicating that CCL27 binds GPR-2. Furthermore, CCL27 induced a strong chemotactic response in GPR-2 transfectants but not on the parental cells (Fig. 2B). Mouse CCL27 desensitized the

response induced by human CCL27 and vice versa (Fig. 2C) dem- http://www.jimmunol.org/ onstrating that they recognize the same receptor. BAF/3 cells are known to express CXCR4 endogenously, so we also tested the ligand of this receptor, CXCL12/SDF-1␣, and observed the ex- pected specific calcium flux in both the transfectants and the parental line. However, the latter response could not be desensitized by CCL27 in the transfectants, indicating that CXCL12 and CCL27 act through different chemokine receptors (Fig. 2C). Taken together, these results indicate that GPR-2 is a receptor for CCL27. Therefore, we have renamed this receptor CCR10, following the by guest on September 26, 2021 established chemokine receptor nomenclature. No other chemokine from a panel of 35 known human chemokines gave a response like CCL27 in the CCR10 transfectants (data not shown). Thus, CCR10 appears to be a specific CCL27 receptor. As mentioned above, transfectants of the cDNA clone encoding the short version (lacking the first 8 aa; Fig. 1) of CCR10 did not respond to CCL27, suggesting that the amino terminus of CCR10 may be important for either receptor translation, stability, transportation to the cell surface, or direct ligand binding. FIGURE 2. CCL27 induced intracellular calcium mobilization and mi- We then explored the expression of CCR10 in cDNA libraries gration in CCR10 transfected BAF/3 cells. A, Dose-dependent intracellular derived from various human organs and cell types by real-time calcium mobilization response on indo-1 AM-loaded BAF/3-hCCR10 quantitative TaqMan PCR. Its expression is highest in the small cells. Right, BAF/3-hCCR10 cells were stimulated with 10, 50, 100, and 200 nM of human CCL27 chemokine. Left, BAF/3-hCCR10 were stimu- intestine and colon, but is also expressed in fetal liver, fetal lung, lated with 10, 50, 100, and 200 nM of murine CCL27 protein. B, Human fetal spleen, fetal testes, fetal brain, and uterus, among other tis- CCL27 induced in vitro migration of hCCR10-transfected BAF/3 cells but sues (data not shown). Moreover, analyses of cDNA libraries from not of parental BAF/3 cells. Mean values from triplicate measures are various activated or resting human T cell clones suggest a complex presented; open bars indicate parental BAF/3 cells; filled bars indicate regulation of this receptor (data not shown). BAF/3-hCCR10 transfectant cells. C, Human CCL27 and murine CCL27 Given that secreted CCL27 is mainly expressed in skin, we in- show cross-desensitization of intracellular calcium mobilization in vestigated the expression of CCR10 and CCL27 in more detail in hCCR10-transfected BAF/3 cells. Top, BAF/3-hCCR10 transfectant cells skin-related tissues including tissue samples from patients with were sequentially stimulated with 200 nM murine CCL27, human CCL27, psoriasis, atopic dermatitis, and cutaneous lupus erythematosus. and human stromal cell-derived factor-1␣ (CXCL12); middle, BAF/3- To this end, we prepared cDNA from total RNA derived from hCCR10 transfectant cells were sequentially stimulated with 200 nM hCCL27, murine CCL27, and human CXCL12; bottom, parental BAF/3 these tissues that we then used for quantitative real-time RT-PCR cells were sequentially stimulated with 200 nM human CCL27, murine analyses. We observed that CCL27 is constitutively and markedly CCL27, and human CXCL12. expressed in normal or inflamed human skin (Fig. 3A). No signif- icant difference in CCL27 expression using real-time quantitative PCR was observed between normal (n ϭ 10) vs lesional skin from chemokine has several unusual features, including a highly re- either psoriatic (n ϭ 21), atopic dermatitis (n ϭ 10), or lupus stricted expression pattern, because it is predominantly expressed erythematosus patients (n ϭ 10). We then analyzed the expression in the skin (3, 4). Our initial experiments failed to detect binding of hCCR10 in these samples (Fig. 3B) and observed uniformly low 3468 CUTTING EDGE Downloaded from

FIGURE 3. Quantitative TaqMan PCR analysis of CCL27 and CCR10 expression in normal vs inflamed skin as well as in cellular constitu- ents of the skin. A and B, Pattern of CCL27 and CCR10 expression in normal skin and lesional skin of psoriatic patients, atopic dermatitis pa- http://www.jimmunol.org/ tients, and lupus erythematosus patients. Values are expressed as femtograms of target gene in 100 ng of total cDNA. Mean Ϯ SD. C, CCL27 and CCR10 mRNA expression in cellular con- stituents of the skin. C, Analysis of CCL27 and CCR10 expression in cDNA obtained from cultured human primary keratinocytes, melanocytes, dermal fibroblasts, dermal microvascular endothelial cells, and epidermal ␥␦ T cells (7-17) by guest on September 26, 2021 treated with medium alone or with TNF-␣/IL-1␤, TNF-␣/IL-1␤/IL-10, IFN-␥, or IL-4 for 6 or 18 h. D, Analysis of CCR10 expression in PBMCs, T cells, dendritic cells derived from CD34ϩ hemopoietic progenitor cells, or monocytes or LC. Values are expressed as femtograms of target gene in 100 ng of total cDNA. Representative data from single donors. The Journal of Immunology 3469 expression, which is not significantly up-regulated in any of the CCL27 is strongly expressed in both normal and inflamed skin. different inflammatory skin conditions. We also studied the ex- This suggests a homeostatic role as discussed above. CCR10 was pression of both CCL27 and CCR10 in various cellular compo- also detected in both normal and diseased skin but at lower levels. nents of the skin (Fig. 3C). CCL27 is exclusively expressed by This is consistent with other chemokine receptors, which, in con- human primary keratinocytes, although its expression is markedly trast to chemokine ligands, do not represent abundant transcripts in up-regulated by IL-1␤ and TNF-␣. Interestingly, IL-1␤/TNF-␣- the expressing cells. Lastly, we should consider the contribution of induced CCL27 mRNA expression was down-regulated by addi- CCR10 expressed by T cells, because we first identified that tional IL-10 treatment (Fig. 3C). In contrast to CCL27, CCR10 is CCL27 preferentially chemoattracts CLAϩ T cells (4). Our data not expressed by keratinocytes (Fig. 3C) but is instead constitu- (Fig. 3) are consistent with the presence of CCR10 in a small tively expressed in human primary melanocytes, dermal fibro- population of peripheral blood T cells, as we predicted from our blasts, and dermal microvascular endothelial cells. It also appears previous studies (4). Future experiments will aim at exploring its to be up-regulated in those cells upon induction with IL-1␤ and role in T cells. In conclusion, we have identified a novel chemo- TNF-␣ (Fig. 3C). We also studied its expression levels in cDNA kine receptor that is likely to be involved in both normal homeosta- derived from PBMCs, T cells, and dendritic cells (Fig. 3D). sis as well as in inflammatory conditions of the skin. CCR10 is expressed in PBMCs, T cells, and LC, but not in either CD34ϩ hemopoietic progenitor-derived or monocyte-derived dendritic cells. Note Added in Proof. Another CC chemokine binding protein has been described in the literature under the aliases D6 or CCR10 (GenBank accession numbers Y12879, U94888, and U92803). Downloaded from However, a signaling function has not been shown for this mole- Discussion cule, and therefore the accepted criteria for a CCR designation have not been met. Accordingly, the Chemokine Receptor Nomen- In this study, we report the identification of a new chemokine clature Committee has recommended that this molecule no longer receptor, which binds the recently described chemokine CTACK be called CCR10 and instead that it be provisionally named D6.

(4), also reported as ILC (3), ALP (5), and Eskine (6) but has now The Committee has recommended (P. Murphy, National Institutes http://www.jimmunol.org/ been renamed CCL27 according to a new systematic chemokine of Health, Bethesda, MD, unpublished data) that the designation nomenclature (18). This new chemokine receptor was the previ- CCR9 be used for the TECK receptor (previous name GPR9-6; ously orphan GPR-2 (8), which has now been renamed CCR10. Of GenBank accession number AJ132337) and that CCR10 be used all the human chemokines we tested, only CCL27 triggered a spe- for the CCL27/CTACK receptor (previous name GPR-2). cific calcium flux and chemotactic responses in CCR10 transfectants, suggesting that CCR10 is a specific receptor for CCL27. The gene encoding CCR10 (GPR-2) has been previously mapped to human chromosome 17q21.1-q21.3 (8). An important feature of Acknowledgments the secreted chemokine form of CCL27 is that it is predominantly by guest on September 26, 2021 We thank Christophe Caux, and Colette Dezutter-Dambuyant for providing expressed in the skin (3, 4) by keratinocytes (4) (Fig. 3C). Inter- cDNAs of LC as well as in vitro-derived dendritic cells and for their help- estingly, CCR10 expression was detected in skin as well as in ful discussion. Furthermore, we thank Leslie McEvoy and Susan Hudak for several other tissues including small intestine, colon, brain, lung, suggestions and discussion. liver, and testes (data not shown). CCL27 has at least two forms (6), but only one bears a signal peptide and is the form associated with predominant skin expression (3, 4). At this point, we do not know if the other intracellular forms of CCL27 bind CCR10 or if References the latter receptor has any role in the physiology of the intracellular 1. Rossi, D. L., A. P. Vicari, K. Franz-Bacon, T. K. McClanahan, and A. 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