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

Loser, Karin; Mehling, Annette; Loeser, Stefanie; Apelt, Jenny; Kuhn, Annegret; Grabbe, Stephan; Schwarz, Thomas; Penninger, Josef; Beissert, Stefan

doi:10.1038/nm1518

Cited by 369 publications

(360 citation statements)

References 45 publications

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“…We found LC morphology to be preserved in RANKL KO mice. Our study extends recent work that described expression of RANK and RANKL in human epidermis (10). Our data clearly indicate that expression of RANKL is not uniform throughout the epidermis, but that maximal levels are present in the suprabasal compartment, precisely where LC reside.…”

Section: Discussionsupporting

confidence: 87%

“…Though no increase in LC apoptosis could be detected by TUNEL in RANKL-deficient epidermis, increased cell death cannot be excluded as cells may migrate out of epidermis before undergoing apoptosis. Interestingly, transgenic overexpression of RANKL expression in epidermis using a keratin 14 promoter system did not affect epidermal LC numbers (10). This paradox may be explained by the supposition that the consequences of RANKL over-activity are carefully controlled in the epidermal microenvironment, either by regulation of cell surface expression of RANK, by increased production of OPG, or by changes in downstream signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

“…This was despite the osteopetrotic phenotype and may be explained by the extramedullary hematopoiesis observed in the liver of RANKL Ϫ/Ϫ mice (8). In the skin, RANKL overexpression has been shown to promote LC activation and to control regulatory T cell homeostasis (10). RANK has been shown to be up-regulated upon DC maturation and RANKL signaling from activated T lymphocytes provides a survival signal to some mature DC subtypes ensuring prolonged cellular interaction and induction of a sufficient immune response (11).…”

Section: Angerhans Cells (Lc)mentioning

confidence: 99%

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Epidermal Receptor Activator of NF-κB Ligand Controls Langerhans Cells Numbers and Proliferation

Barbaroux

Beleut

Brisken

et al. 2008

The Journal of Immunology

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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-κB 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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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Angerhans Cells (Lc)mentioning

confidence: 99%

See 1 more Smart Citation

Epidermal Receptor Activator of NF-κB Ligand Controls Langerhans Cells Numbers and Proliferation

Barbaroux

Beleut

Brisken

et al. 2008

The Journal of Immunology

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“…135 Furthermore, keratinocytes in an inflammatory environment express high levels of the receptor activator of nuclear factor KB ligand (RANKL) that induces the expression of CD205 and CD86 in LC when it binds to the receptor activator of nuclear factor KB (RANK). 136 The expression of CD205 is associated with the induction of CD4CD25 cells, which suppress the immune response. 137 …”

Section: Keratinocytesmentioning

confidence: 99%

Imunopatologia da dermatite de contato alérgica

Martins

Reis

2011

An. Bras. Dermatol.

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Allergic contact dermatitis is the consequence of an immune reaction mediated by T cells against low molecular weight chemicals known as haptens. It is a common condition that occurs in all races and age groups and affects the quality of life of those who present it. The immunological mechanism of this disease has been reviewed in recent decades with significant advance in its understanding. The metabolism and pathway of the haptens as well as the activation and mechanism of action of the cells responsible for both the immune reaction and its completion are discussed in this article. Keywords: Allergy and immunology; Dermatitis, allergic contact; Dermatitis, contact; Hypersensitivity Resumo: A dermatite de contato alérgica é consequência de uma reação imune mediada por células T contra químicos de baixo peso molecular, denominados haptenos. É uma condição frequente que ocorre em todas as raças e faixas etárias e afeta a qualidade de vida de seus portadores. O mecanismo imunológico desta doença vem sendo revisto nas últimas décadas com significativo avanço no seu entendimento. A metabolização e o caminho dos haptenos, bem como a formação e o mecanismo de ação das células responsáveis tanto pela reação quanto pelo seu término, são discutidos neste artigo. Palavras-chave: Alergia e imunologia; Hipersensibilidade; Dermatite de contato; Dermatites alérgicas de contato

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“…UV light up-regulates the expression by skin keratinocytes of the ligand to receptor activator of NFjB (RANK), which then interacts with RANK + Langerhans cells to promote the proliferation of T reg [30]. Physiological levels of hormones such as estrogens can induce T reg [31].…”

Section: Tissue Regulation Of T Regmentioning

confidence: 99%

Regulatory T cells and immune computation

Quintana

Cohen

2008

Eur J Immunol

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The role of Treg in immune regulation is the topic of this Viewpoint series in the European Journal of Immunology (EJI); the question to be discussed in this section is the effector function of Treg in immune regulation. In this manuscript, we take on the following three postulates outlined by Rolf Zinkernagel on the role of Treg in the control of immunity. First, the immune response is regulated primarily by the antigen and not by Treg. Second, immune non‐responsiveness results from the deletion of specific receptor‐bearing T cells. Third, there is no definitive proof of the existence of specialized Treg that know what is needed for an equilibrated immune response. Herein, we discuss data demonstrating the existence of specialized Treg and therefore arguing against the validity of the first two postulates. However, based on the reactive nature of the immune system, we agree with Rolf’s third postulate in that Treg cannot know ahead of time an ideal set‐point for immune homeostasis. See accompanying commentary:

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

Cited by 369 publications

References 45 publications

Epidermal Receptor Activator of NF-κB Ligand Controls Langerhans Cells Numbers and Proliferation

Epidermal Receptor Activator of NF-κB Ligand Controls Langerhans Cells Numbers and Proliferation

Imunopatologia da dermatite de contato alérgica

Regulatory T cells and immune computation

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