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CCL27–CCR10 interactions regulate T cell–mediated skin inflammation

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.

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Figure 1: CCL27 and CCR10 expression in normal and inflamed skin.
Figure 2: Kinetics of human CCL27 and CCR10 expression during the elicitation of nickel-specific allergic skin reactions.
Figure 3: CCL27 binds to the surface of endothelial cells and fibroblasts.
Figure 4: CCR10 is expressed on a subset of circulating skin-homing CLA+ T cells, dermal microvascular endothelial cells and dermal fibroblasts.
Figure 5: CCL27 is regulated by TNF-α and IL-1β.
Figure 6: Neutralization of CCL27–CCR10 interactions impair antigen-specific skin immune responses.

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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.

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Correspondence to Bernhard Homey or Albert Zlotnik.

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A. Zlotnick holds shares of Schering-Plough, Inc., Medarex and Incyte Genomics. A. Zlotnick is also Director of Genomic Medicine at EOS Biotechnology.

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Note: Supplementary information is available on the Nature Medicine website (http://medicine.nature.com/supplementary_info/).

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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

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