Abstract
The skin-associated chemokine CCL27 (also called CTACK, ALP and ESkine) and its receptor CCR10 (GPR-2) mediate chemotactic responses of skin-homing T cells in vitro. Here we report that most skin-infiltrating lymphocytes in patients suffering from psoriasis, atopic or allergic-contact dermatitis express CCR10. Epidermal basal keratinocytes produced CCL27 protein that bound to extracellular matrix, mediated adhesion and was displayed on the surface of dermal endothelial cells. Tumor necrosis factor-α and interleukin-1β induced CCL27 production whereas the glucocorticosteroid clobetasol propionate suppressed it. Circulating skin-homing CLA+ T cells, dermal microvascular endothelial cells and fibroblasts expressed CCR10 on their cell surface. In vivo, intracutaneous CCL27 injection attracted lymphocytes and, conversely, neutralization of CCL27–CCR10 interactions impaired lymphocyte recruitment to the skin leading to the suppression of allergen-induced skin inflammation. Together, these findings indicate that CCL27–CCR10 interactions have a pivotal role in T cell–mediated skin inflammation.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Schon, M.P., Detmar, M. & Parker, C.M. Murine psoriasis-like disorder induced by naive CD4+ T cells. Nature Med. 3, 183–188 (1997).
Schon, M.P. Animal models of psoriasis—what can we learn from them? J. Invest. Dermatol. 112, 405–10 (1999).
Nickoloff, B.J. et al. Is psoriasis a T-cell disease? Exp. Dermatol. 9, 359–375 (2000).
Leung, D.Y. & Soter, N.A. Cellular and immunologic mechanisms in atopic dermatitis. J. Am. Acad. Dermatol. 44, S1–S12 (2001).
Woodward, A. L. et al. An obligate role for T-cell receptor αβ+ T cells but not T-cell receptor γΦ+ T cells, B cells, or CD40/CD40L interactions in a mouse model of atopic dermatitis. J. Allergy Clin. Immunol. 107, 359–366 (2001).
Grabbe, S. & Schwarz, T. Immunoregulatory mechanisms involved in elicitation of allergic contact hypersensitivity. Immunol. Today 19, 37–44 (1998).
Picker, L.J. et al. Differential expression of homing-associated adhesion molecules by T cell subsets in man. J. Immunol. 145, 3247–3255 (1990).
Santamaria, L.F., Perez Soler, M.T., Hauser, C. & Blaser, K. Allergen specificity and endothelial transmigration of T cells in allergic contact dermatitis and atopic dermatitis are associated with the cutaneous lymphocyte antigen. Int. Arch. Allergy Immunol. 107, 359–362 (1995).
Zlotnik, A. & Yoshie, O. Chemokines: A new classification system and their role in immunity. Immunity 12, 121–127 (2000).
Homey, B. & Zlotnik, A. Chemokines in allergy. Curr. Opin. Immunol. 11, 626–634 (1999).
Morales, J. et al. CTACK, a skin-associated chemokine that preferentially attracts skin-homing memory T cells. Proc. Natl. Acad. Sci. USA 96, 14470–14475 (1999).
Homey, B. et al. Cutting edge: the orphan chemokine receptor G protein-coupled receptor-2 (GPR-2, CCR10) binds the skin-associated chemokine CCL27 (CTACK/ALP/ILC). J. Immunol. 164, 3465–3470 (2000).
Witt, D.P. & Lander, A.D. Differential binding of chemokines to glycosaminoglycan subpopulations. Curr. Biol. 4, 394–400 (1994).
Webb, L.M., Ehrengruber, M.U., Clark-Lewis, I., Baggiolini, M. & Rot, A. Binding to heparan sulfate or heparin enhances neutrophil responses to interleukin 8. Proc. Natl. Acad. Sci. USA 90, 7158–7162 (1993).
Proudfoot, A.E. et al. The BBXB motif of RANTES is the principal site for heparin binding and controls receptor selectivity. J. Biol. Chem. 276, 10620–10626 (2001).
Jarmin, D.I. et al. Cutting edge: identification of the orphan receptor G-protein-coupled receptor 2 as CCR10, a specific receptor for the chemokine ESkine. J. Immunol. 164, 3460–3464 (2000).
Ruzicka, T., Assmann, T. & Homey, B. Tacrolimus: the drug for the turn of the millennium? Arch. Dermatol. 135, 574–580 (1999).
Ruzicka, T. et al. A short-term trial of tacrolimus ointment for atopic dermatitis. European Tacrolimus Multicenter Atopic Dermatitis Study Group. N. Engl. J. Med. 337, 816–821 (1997).
Spergel, J. M. et al. Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice. J. Clin. Invest. 101, 1614–1622 (1998).
Spergel, J. M., Mizoguchi, E., Oettgen, H., Bhan, A. K. & Geha, R. S. Roles of TH1 and TH2 cytokines in a murine model of allergic dermatitis. J. Clin. Invest. 103, 1103–1111 (1999).
Bos, J.D., de Boer, O.J., Tibosch, E., Das, P.K. & Pals, S.T. Skin-homing T lymphocytes: detection of cutaneous lymphocyte-associated antigen (CLA) by HECA-452 in normal human skin. Arch. Dermatol. Res. 285, 179–183 (1993).
Picker, L.J., Michie, S.A., Rott, L.S. & Butcher, E.C. A unique phenotype of skin-associated lymphocytes in humans. Preferential expression of the HECA-452 epitope by benign and malignant T cells at cutaneous sites. Am. J. Pathol. 136, 1053–1068 (1990).
Rot, A. Endothelial cell binding of NAP-1/IL-8: role in neutrophil emigration. Immunol. Today 13, 291–294 (1992).
Springer, T. A. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76, 301–314 (1994).
Cinamon, G., Shinder, V. & Alon, R. Shear forces promote lymphocyte migration across vascular endothelium bearing apical chemokines. Nature Immunol. 2, 515–522 (2001).
Middleton, J. et al. Transcytosis and surface presentation of IL-8 by venular endothelial cells. Cell 91, 385–395 (1997).
Baekkevold, E.S. et al. The ccr7 ligand elc (ccl19) is transcytosed in high endothelial venules and mediates t cell recruitment. J. Exp. Med. 193, 1105–1112 (2001).
Grabovsky, V. et al. Subsecond induction of α4 integrin clustering by immobilized chemokines stimulates leukocyte tethering and rolling on endothelial vascular cell adhesion molecule 1 under flow conditions. J. Exp. Med. 192, 495–506 (2000).
Tanaka, Y. et al. T-cell adhesion induced by proteoglycan-immobilized cytokine MIP-1 β. Nature 361, 79–82 (1993).
Rot, A. et al. Some aspects of IL-8 pathophysiology. III: Chemokine interaction with endothelial cells. J. Leukoc. Biol. 59, 39–44 (1996).
Bondeson, J. & Maini, R.N. Tumour necrosis factor as a therapeutic target in rheumatoid arthritis and other chronic inflammatory diseases: the clinical experience with infliximab (REMICADE). Int. J. Clin. Pract. 55, 211–216 (2001).
Kirby, B., Marsland, A.M., Carmichael, A.J. & Griffiths, C.E. Successful treatment of severe recalcitrant psoriasis with combination infliximab and methotrexate. Clin. Exp. Dermatol. 26, 27–29 (2001).
Reiss, Y., Proudfoot, A.E., Power, C.A., Campbell, J.J. & Butcher, E.C. CC chemokine receptor (CCR)4 and the CCR10 ligand cutaneous T cell–attracting chemokine (CTACK) in lymphocyte trafficking to inflamed skin. J. Exp. Med. 194, 1541–1547 (2001).
Butcher, E.C. & Picker, L.J. Lymphocyte homing and homeostasis. Science 272, 60–66 (1996).
Campbell, J.J. et al. The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells. Nature 400, 776–780 (1999).
Andrew, D.P. et al. C-C chemokine receptor 4 expression defines a major subset of circulating nonintestinal memory T cells of both Th1 and Th2 potential. J. Immunol. 166, 103–111 (2001).
Goebeler, M. et al. The C-X-C chemokine Mig is highly expressed in the papillae of psoriatic lesions. J. Pathol. 184, 89–95 (1998).
Gottlieb, A.B., Luster, A.D., Posnett, D.N. & Carter, D.M. Detection of aγ interferon-induced protein IP-10 in psoriatic plaques. J. Exp. Med. 168, 941–948 (1988).
Homey, B. et al. Up-regulation of macrophage inflammatory protein-3 α/CCL20 and CC chemokine receptor 6 in psoriasis. J. Immunol. 164, 6621–6632 (2000).
Tsai, J.C. et al. Permeability barrier disruption alters the localization and expression of TNF α/protein in the epidermis. Arch. Dermatol. Res. 286, 242–248 (1994).
Wood, L.C., Jackson, S.M., Elias, P.M., Grunfeld, C. & Feingold, K.R. Cutaneous barrier perturbation stimulates cytokine production in the epidermis of mice. J. Clin. Invest. 90, 482–487 (1992).
Piguet, P.F. TNF and the pathology of the skin. Res. Immunol. 144, 320–326 (1993).
Sprecher, E. & Becker, Y. Detection of IL-1β, TNF-α, and IL-6 gene transcription by the polymerase chain reaction in keratinocytes, Langerhans cells and peritoneal exudate cells during infection with herpes simplex virus-1. Arch. Virol 126, 253–269 (1992).
Muller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001).
Hong, K., Chu, A., Ludviksson, B.R., Berg, E.L. & Ehrhardt, R.O. IL-12, independently of IFN-γ, plays a crucial role in the pathogenesis of a murine psoriasis-like skin disorder. J. Immunol. 162, 7480–7491 (1999).
Acknowledgements
We would like to thank H. Kanzler for discussions; M. Koivuluhta and V. Paavola for help with tissue procurement and histology; and R. deWaal Malefyt for establishing the real time quantitative PCR at the DNAX Research Institute. This work was supported by a grant of the Deutsche Forschungsgemeinschaft (to B.H.; Ho 2019/1-1). DNAX Research Institute is a subsidiary of the Schering–Plough Corporation.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
A. Zlotnick holds shares of Schering-Plough, Inc., Medarex and Incyte Genomics. A. Zlotnick is also Director of Genomic Medicine at EOS Biotechnology.
Additional information
Note: Supplementary information is available on the Nature Medicine website (http://medicine.nature.com/supplementary_info/).
Supplementary information
Rights and permissions
About this article
Cite this article
Homey, B., Alenius, H., Müller, A. et al. CCL27–CCR10 interactions regulate T cell–mediated skin inflammation. Nat Med 8, 157–165 (2002). https://doi.org/10.1038/nm0202-157
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nm0202-157
This article is cited by
-
Systemic immune profile in Prader-Willi syndrome: elevated matrix metalloproteinase and myeloperoxidase and reduced macrophage inhibitory factor
Orphanet Journal of Rare Diseases (2023)
-
IgE-binding monocytes upregulate the coagulation cascade in allergic horses
Genes & Immunity (2023)
-
Transcriptomic profiling of pemphigus lesion infiltrating mononuclear cells reveals a distinct local immune microenvironment and novel lncRNA regulators
Journal of Translational Medicine (2022)
-
Comparative transcriptome in large-scale human and cattle populations
Genome Biology (2022)
-
Elevated G-CSF, IL8, and HGF in patients with definite Meniere’s disease may indicate the role of NET formation in triggering autoimmunity and autoinflammation
Scientific Reports (2022)