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-kappaB (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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RANK activation of Langerhans cells by UV can induce pro-survival and anti-apoptotic signals due to upregulation of Bcl-xL, leading to generation of regulatory T cells.
“Intriguingly, receptor activator of NF-κB (RANK) activation of LCs by UV can induce the pro-survival and anti-apoptotic signals due to the upregulation of Bcl-xL, leading to the generation of regulatory T cells.”
From Molecular Mechanisms of UV-Induced Apoptosis and Its Effects on Skin Residential Cells: The Implication in UV-Based Phototherapy (2013) · cites this paper as [65]
UV-exposed Langerhans cells have a high level of RANK, which can potently induce activation of Treg cells in vitro.
“These UV-exposed LCs have a high level of RANK, which can potently induce activation of Treg cells in vitro[65].”
From Molecular Mechanisms of UV-Induced Apoptosis and Its Effects on Skin Residential Cells: The Implication in UV-Based Phototherapy (2013) · cites this paper as [65]
The capacity of Langerhans cells to induce Treg cells is dependent on the activation of RANK on epidermal Langerhans cells through its ligand RANKL on keratinocytes.
“Loser et al. demonstrated that the capacity of LCs to induce Treg cells is dependent on the activation of receptor activator of NF-κB (RANK) on the epidermal LCs through its ligand RANKL, also known as CD254, OPGL and TRANCE on keratinocytes [65].”
From Molecular Mechanisms of UV-Induced Apoptosis and Its Effects on Skin Residential Cells: The Implication in UV-Based Phototherapy (2013) · cites this paper as [65]
Langerhans cells are critical to the generation of Treg cells.
“Actually, LCs are critical to the generation of Treg cells [65].”
From Molecular Mechanisms of UV-Induced Apoptosis and Its Effects on Skin Residential Cells: The Implication in UV-Based Phototherapy (2013) · cites this paper as [65]
Defects in immune surveillance might result from the generation of tolerogenic LCs or dermal dendritic cells by UV-induced apoptotic cells, with subsequent activation of Treg cells and depletion of CD8+ T cells.
“The defects in immune surveillance might result from the generation of tolerogenic LCs or dermal dendritic cells [125] by UV-induced apoptotic cells, with subsequent activation of Treg cells and depletion of CD8+ T cells [65].”
From Molecular Mechanisms of UV-Induced Apoptosis and Its Effects on Skin Residential Cells: The Implication in UV-Based Phototherapy (2013) · cites this paper as [65]
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References 47 · Cited by 402
- Authors
- Loser, K., Mehling, A., Loeser, S., Apelt, J., Kuhn, A., Grabbe, S., Schwarz, T., Penninger, J. M., & Beissert, S.
- Affiliations
- University of Münster (DE)
- Institute of Molecular Biotechnology (AT)
- German Cancer Research Center (DE)
- University of Duisburg-Essen (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- Corresponding author
- Beissert, Stefan
- Venue
- Nature Medicine
- Published
- 2006-12
- Volume
- 12
- Issue
- 12
- Pages
- 1372-1379
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2056139144
- Cited by
- 402
- References
- 47
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 11 · 2023: 11 · 2022: 9 · 2021: 11 · 2020: 16 · 2019: 10 · 2018: 17 · 2017: 21 · 2016: 28 · 2015: 20 · 2014: 21 · 2013: 25 · 2012: 31
- FWCI
- 10.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
- Keywords
- RANKL, RANK, regulatory T cells, keratinocytes, Langerhans cells, CD4+CD25+ T cells, contact allergy, systemic autoimmunity, skin inflammation
- MeSH terms
- Epidermal Cells, Animals, Cell Count, Dendritic Cells, Epidermis, Immune Tolerance, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Transgenic, Ultraviolet Rays, Autoimmunity, T-Lymphocytes, Regulatory, Mice, RANK Ligand
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