Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells

Abstract

Regulatory CD4+CD25+ T cells are important in suppressing immune responses. The requirements for the maintenance of peripheral CD4+CD25+ T cells remain incompletely understood. Receptor activator of NF-κB (RANK) and its ligand (RANKL; also known as CD254, OPGL and TRANCE) are key regulators of bone remodeling, mammary gland formation, lymph node development and T-cell/dendritic cell communication. Here we report that RANKL is expressed in keratinocytes of the inflamed skin. RANKL overexpression in keratinocytes resulted in functional alterations of epidermal dendritic cells and systemic increases of regulatory CD4+CD25+ T cells. Thus, epidermal RANKL expression can change dendritic cell functions to maintain the number of peripheral CD4+CD25+ regulatory T cells. Epidermal RANKL mediated ultraviolet-induced immunosuppression and overexpression of epidermal RANKL suppressed allergic contact hypersensitivity responses and the development of systemic autoimmunity. Therefore, environmental stimuli at the skin can rewire the local and systemic immune system by means of RANKL.

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Figure 1: Epidermal RANKL overexpression suppresses cutaneous contact hypersensitivity (CHS) responses.
Figure 2: Epidermal RANKL controls the number of peripheral CD4+CD25+ regulatory T cells.
Figure 3: Epidermal Langerhans cells control systemic homeostasis of CD4+CD25+ regulatory T cells.
Figure 4: Phenotypic and functional differences between Langerhans cells from wild-type and K14-RANKL Tg mice.
Figure 5: Epidermal RANKL suppressed CD40L-induced systemic autoimmunity.
Figure 6: RANKL mediates ultraviolet-induced immunosuppression.

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Acknowledgements

We thank M. Voskort and B. Geng for technical assistance. The Tnfs11 (Rankl) cDNA was provided by L. Galibert (Immunex), and the antibody to CD207 by S. Saeland (Institut National de la Santé et de la Recherche Médicale (INSERM) Lyon). This work was supported by the German Research Association (SFB 293, BE 1580/6-2 and BE 1580/7-1 to S.B.; KU 1559/1-1 to A.K.), the Interdisciplinary Center of Clinical Research (Lo2/017/07 to K.L. and S.B.), and by the Innovative Medical Research fund of the University of Münster Medical School (Lo11/06 03 to K.L. and S.B.). J.M.P. is supported by grants from the Austrian National Bank, the Austrian Academy of Sciences, the Austrian Ministry of Science and Education, the 6th EU framework (EuroThymaide), an EU Marie Curie Excellence grant, and a program project grant from the Austrian Fonds zur Foerderung der Wissenschaftlichen Forschung (FWF).

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K.L. performed cell-culture experiments and animal experiments, generated figures, and helped to write the manuscript. A.M. generated the K14-RANKL Tg transgenic mouse strains. S.L. bred and provided the Tnfs11−/− mice. J.A. assisted with human immunofluorescence experiments. A.K. assisted with skin samples and provided expertise in immunohistochemistry. S.G. provided methodological expertise and helped design some experiments. T.S. provided expertise in ultraviolet animal experiments. J.M.P. analyzed the data and helped design the study and write the manuscript. S.B. (principal investigator) designed the experiments, interpreted and analyzed data, and drafted and edited the manuscript.

Corresponding author

Correspondence to Stefan Beissert.

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Supplementary information

Supplementary Fig. 1

Systemic administration of mometason fuorate or in vitro mometason fuorate-treatment does not affect T cells. (PDF 88 kb)

Supplementary Fig. 2

Blocking the RANK-RANKL signaling pathway restores suppression of contact hypersensitivity responses by UV-irradiation. (PDF 55 kb)

Supplementary Methods (PDF 43 kb)

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Loser, K., Mehling, A., Loeser, S. et al. Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells. Nat Med 12, 1372–1379 (2006). https://doi.org/10.1038/nm1518

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