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.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Cavani, A. et al. Human CD25+ regulatory T cells maintain immune tolerance to nickel in healthy, nonallergic individuals. J. Immunol. 171, 5760–5768 (2003).
Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995).
Viglietta, V., Baecher-Allan, C., Weiner, H.L. & Hafler, D.A. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J. Exp. Med. 199, 971–979 (2004).
Fontenot, J.D., Gavin, M.A. & Rudensky, A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).
Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).
Itoh, M. et al. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J. Immunol. 162, 5317–5326 (1999).
Malek, T.R., Yu, A., Vincek, V., Scibelli, P. & Kong, L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rβ-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17, 167–178 (2002).
Papiernik, M., de Moraes, M.L., Pontoux, C., Vasseur, F. & Penit, C. Regulatory CD4 T cells: expression of IL-2R α chain, resistance to clonal deletion and IL-2 dependency. Int. Immunol. 10, 371–378 (1998).
Salomon, B. et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12, 431–440 (2000).
Yamazaki, S. et al. Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen-processing dendritic cells. J. Exp. Med. 198, 235–247 (2003).
Jonuleit, H., Schmitt, E., Schuler, G., Knop, J. & Enk, A.H. Induction of interleukin 10-producing, nonproliferating CD4+ T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J. Exp. Med. 192, 1213–1222 (2000).
Mehling, A. et al. Overexpression of CD40 ligand in murine epidermis results in chronic skin inflammation and systemic autoimmunity. J. Exp. Med. 194, 615–628 (2001).
Anderson, D.M. et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390, 175–179 (1997).
Wong, B.R. et al. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J. Biol. Chem. 272, 25190–25194 (1997).
Theill, L.E., Boyle, W.J. & Penninger, J.M. RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu. Rev. Immunol. 20, 795–823 (2002).
Fata, J.E. et al. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103, 41–50 (2000).
Grabbe, S. & Schwarz, T. Immunoregulatory mechanisms involved in elicitation of allergic contact hypersensitivity. Immunol. Today 19, 37–44 (1998).
Sakaguchi, S. et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol. Rev. 182, 18–32 (2001).
Laufer, T.M., DeKoning, J., Markowitz, J.S., Lo, D. & Glimcher, L.H. Unopposed positive selection and autoreactivity in mice expressing class II MHC only on thymic cortex. Nature 383, 81–85 (1996).
Read, S., Malmstrom, V. & Powrie, F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+CD4+ regulatory cells that control intestinal inflammation. J. Exp. Med. 192, 295–302 (2000).
Lehmann, J. et al. Expression of the integrin α Eβ 7 identifies unique subsets of CD25+ as well as CD25- regulatory T cells. Proc. Natl. Acad. Sci. USA 99, 13031–13036 (2002).
Bruder, D. et al. Neuropilin-1: a surface marker of regulatory T cells. Eur. J. Immunol. 34, 623–630 (2004).
Shevach, E.M. CD4+ CD25+ suppressor T cells: more questions than answers. Nat. Rev. Immunol. 2, 389–400 (2002).
Cremer, I. et al. Long-lived immature dendritic cells mediated by TRANCE-RANK interaction. Blood 100, 3646–3655 (2002).
Banchereau, J. & Steinman, R.M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).
Steinman, R.M., Hawiger, D. & Nussenzweig, M.C. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711 (2003).
Loser, K. et al. Enhanced contact hypersensitivity and antiviral immune responses in vivo by keratinocyte-targeted overexpression of IL-15. Eur. J. Immunol. 34, 2022–2031 (2004).
Mahnke, K., Quian, Y., Knop, J. & Enk, A.H. Induction of CD4+CD25+ regulatory T cells by targeting of antigens to immature dendritic cells. Blood 101, 4862–4869 (2003).
Salomon, B. et al. Development of spontaneous autoimmune peripheral polyneuropathy in B7–2-deficient NOD mice. J. Exp. Med. 194, 677–684 (2001).
Dombrecht, E.J. et al. Influence of anti-tumor necrosis factor therapy (Adalimumab) on regulatory T cells and dendritic cells in rheumatoid arthritis. Clin. Exp. Rheumatol. 24, 31–37 (2006).
Bynoe, M.S., Evans, J.T., Viret, C. & Janeway, C.A., Jr. Epicutaneous immunization with autoantigenic peptides induces T suppressor cells that prevent experimental allergic encephalomyelitis. Immunity 19, 317–328 (2003).
Geissmann, F. et al. Accumulation of immature Langerhans cells in human lymph nodes draining chronically inflamed skin. J. Exp. Med. 196, 417–430 (2002).
Scheinecker, C., McHugh, R., Shevach, E.M. & Germain, R.N. Constitutive presentation of a natural tissue autoantigen exclusively by dendritic cells in the draining lymph node. J. Exp. Med. 196, 1079–1090 (2002).
Schwarz, A. et al. Ultraviolet radiation-induced regulatory T cells not only inhibit the induction but can suppress the effector phase of contact hypersensitivity. J. Immunol. 172, 1036–1043 (2004).
Kong, Y.Y. et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315–323 (1999).
Ashcroft, A.J. et al. Colonic dendritic cells, intestinal inflammation, and T cell-mediated bone destruction are modulated by recombinant osteoprotegerin. Immunity 19, 849–861 (2003).
Green, E.A., Choi, Y. & Flavell, R.A. Pancreatic lymph node-derived CD4+CD25+ Treg cells: highly potent regulators of diabetes that require TRANCE-RANK signals. Immunity 16, 183–191 (2002).
Kragballe, K. Vitamin D analogues in the treatment of psoriasis. J. Cell. Biochem. 49, 46–52 (1992).
Barrat, F.J. et al. In vitro generation of interleukin 10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J. Exp. Med. 195, 603–616 (2002).
Leung, D.Y., Boguniewicz, M., Howell, M.D., Nomura, I. & Hamid, Q.A. New insights into atopic dermatitis. J. Clin. Invest. 113, 651–657 (2004).
Kuhn, A. et al. Phototesting in lupus erythematosus: a 15-year experience. J. Am. Acad. Dermatol. 45, 86–95 (2001).
Vassar, R., Rosenberg, M., Ross, S., Tyner, A. & Fuchs, E. Tissue-specific and differentiation-specific expression of a human K14 keratin gene in transgenic mice. Proc. Natl. Acad. Sci. USA 86, 1563–1567 (1989).
Loser, K. et al. FK506 controls CD40L-induced systemic autoimmunity in mice. J. Invest. Dermatol. 126, 1307–1315 (2006).
Loser, K. et al. In vitro-generated regulatory T cells induced by Foxp3-retrovirus infection control murine contact allergy and systemic autoimmunity. Gene Ther. 12, 1294–1304 (2005).
Setoguchi, R., Hori, S., Takahashi, T. & Sakaguchi, S. Homeostatic maintenance of natural Foxp3+CD25+CD4+ regulatory T cells by interleukin(IL)-2 and induction of autoimmune disease by IL-2 neutralization. J. Exp. Med. 201, 723–735 (2005).
Labeur, M.S. et al. Generation of tumor immunity by bone marrow-derived dendritic cells correlates with dendritic cell maturation stage. J. Immunol. 162, 168–175 (1999).
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).
A patent based on our findings has been filed.
Systemic administration of mometason fuorate or in vitro mometason fuorate-treatment does not affect T cells. (PDF 88 kb)
Blocking the RANK-RANKL signaling pathway restores suppression of contact hypersensitivity responses by UV-irradiation. (PDF 55 kb)
About this article
Cite this article
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
Photochemical & Photobiological Sciences (2020)
Ameliorative effect of green odor against UVB ‐induced immunosuppression of contact hypersensitivity
Dermatologic Therapy (2020)
Inflammation and Regeneration (2020)
Journal of Anatomy (2019)