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B Ligand Controls Langerhans Cells Numbers and Proliferation1,2
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* St. John’s Institute of Dermatology, King’s College London, London, United Kingdom;
Ecole Polytechnique Fédérale de Lausanne, Institut Suisse de Recherches Experimentales sur le Cancer, Lausanne, Switzerland;
National Center of Competence in Research Molecular Oncology, Lausanne, Switzerland;
Centre National de la Recherche Scientifique Laboratory of Therapeutic Immunology and Chemistry, Institut de Biologie Moléculaire et Cellulaire, Université Louis Pasteur, Strasbourg, France; and
¶ National Institute for Health Research Biomedical Research Centre at Guy’s and St. Thomas’ National Health Service Foundation Trust and King’s College London, London, United Kingdom
Langerhans cells (LC) are the dendritic APC population of the epidermis, where they reside for long periods and are self-replicating. The molecular signals underlying these characteristics are unknown. The TNF superfamily member receptor activator of NF-
B ligand (RANKL, TNFSF11) has been shown to sustain viability of blood dendritic cells in addition to its role in promoting proliferation and differentiation of several cell types, notably osteoclasts. In this study, we have studied expression of the RANKL system in skin and have defined a key role for this molecule in LC homeostasis. In vitro and in vivo, human KC expressed RANKL and epidermal LC expressed cell surface RANK. In vitro, RANKL sustained CD34+ progenitor-derived LC viability following 72-h cultures in cytokine-free medium (79.5 ± 1% vs 55.2 ± 5.7% live cells, respectively; n = 4; p < 0.05). In vivo, RANKL-deficient mice displayed a marked reduction in epidermal LC density (507.1 ± 77.2 vs 873.6 ± 41.6 LC per mm2; n = 9; p < 0.05) and their proliferation was impaired without a detectable effect on apoptosis. These data indicate a key role for the RANKL system in the regulation of LC survival within the skin and suggest a regulatory role for KC in the maintenance of epidermal LC homeostasis.
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1 This work was supported by the Chelsea and Westminster Hospital Special Trustees and Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre award to Guy’s and St. Thomas’ National Health Service Foundation Trust in partnership with King’s College London. Financial support was also provided by Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, and Association pour la Recherche sur le Cancer.
2 J.-B.O.B. designed and performed the research and drafted the manuscript, M.B. performed the research, C.B. provided reagents, C.G.M. designed the research and drafted the manuscript, and R.W.G. designed the research and drafted the manuscript.
3 Address correspondence and reprint requests to Dr. Jean-Baptiste Barbaroux, St. John’s Institute of Dermatology, Guy’s Hospital, London SE1 9RT, U.K. E-mail address: jean-baptiste.barbaroux{at}kcl.ac.uk
4 Abbreviations used in this paper: LC, Langerhans cell; DC, dendritic cell; KC, keratinocyte; LCL-DC, LC-like DC; OPG, Osteoprotegerin; RANK, receptor activator of NF-B; KO, knockout; PI, propidium iodide; CS, cytokine supplemented; WT, wild type.
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