Langerhans Cells Are Required for UVR-Induced Immunosuppression

Schwarz, Agatha; Noordegraaf, Mirko; Maeda, Akira; Torii, Kan; Clausen, Björn E.; Schwarz, Thomas

doi:10.1038/jid.2009.429

Cited by 132 publications

(112 citation statements)

References 57 publications

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“…Depletion of murine LCs was attributed to apoptosis of LCs induced by GCS (56, 16), which was confirmed in patients with atopic dermatitis upon topical GCS treatment (57). Consequently, prevention of CHS in mice by topical GCS was found to be independent of Tregs (16). Our data of increased levels of LCs with Tregpromoting capacity upon oral GCS treatment compared with that of lesions prior to GCS therapy are seemingly different.…”

Section: Discussionmentioning

confidence: 62%

“…In murine LC knockout models, LCs were dispensable for the development of CHS reactions (50) or even exhibited downregulatory properties (51). Induction of Tregs, as observed in different murine models of CHS (16)(17)(18) and in patients with LC histiocytosis (52), is one possibility for the tolerogenic potential of LCs. In this study, we show for the first time to our knowledge that treatment of contact-allergic patients with oral GCS endows LCs with Tregenhancing properties.…”

Section: Discussionmentioning

confidence: 99%

“…This is also true for epidermal Langerhans cells (LCs) (16)(17)(18). In mice, the interaction of the receptor activator for NF-kB (RANK) with its ligand (RANKL), originally described as regulators of bone remodeling and T cell/DC communication (19), is apparently crucial for the induction of regulatory T cells (Tregs) by LCs (17,18).…”

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confidence: 99%

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Glucocorticosteroids Modify Langerhans Cells To Produce TGF-β and Expand Regulatory T Cells

Stary

Klein

Bauer

et al. 2011

The Journal of Immunology

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Although glucocorticosteroids (GCSs) have been used for many decades in transplantation and (auto)inflammatory diseases, the exact mechanisms responsible for their immunosuppressive properties are not fully understood. The purpose of this study was to characterize the effects of oral GCSs on the cutaneous immune response. We analyzed, by immunofluorescence staining and quantitative RT-PCR, residual skin biopsy material from a clinical study in which we had used oral GCS as positive control for determining the effects of candidate anti-inflammatory compounds on epicutaneous patch tests of Ni-allergic patients. Expectedly, oral GCS treatment led to a reduction of clinical symptoms and infiltrating leukocytes. Notably, we observed increased numbers of dermal FOXP3+CD25+ T cells and epidermal Langerhans cells (LCs) that were associated with upregulated mRNA expression of TGF-β in lesions of GCS-treated Ni-allergic patients. To investigate this phenomenon further, we exposed purified LCs to GCS. They exhibited, in contrast to GCS-nonexposed LCs, 1) a more immature phenotype, 2) higher intracellular amounts of TGF-β, and 3) increased receptor activator for NF-κB expression, conditions that reportedly favor the expansion of regulatory T cells (Tregs). Indeed, we observed an enhancement of functionally suppressive FOXP3+ T cells when CD3+ cells were incubated with GCS-pretreated LCs. The expansion of Tregs was inhibited by TGF-β blockage alone, and their suppressive activity was neutralized by a combination of anti–TGF-β and anti–IL-10 Abs. Our data show that systemically applied GCSs endow LCs with Treg-promoting properties and thus shed new light on the mechanisms of GCS-mediated immunosuppression.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

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Glucocorticosteroids Modify Langerhans Cells To Produce TGF-β and Expand Regulatory T Cells

Stary

Klein

Bauer

et al. 2011

The Journal of Immunology

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“…32 The deleterious influence of UVR on effector T-cell activation contrasts with the induction of regulatory T cells (T reg ) by photodamaged LCs, resulting in antigen-specific immunotolerance rather than sensitization. 32,42,43 It leads to an immunosuppressive positive feedback loop, where T reg negatively influence antigen presentation to effector T cells. 29 UV exposure also affects LCs' capacity to stimulate different subsets of CD4 + T-cell clones; this results in preferential suppression of T h1 -mediated immune responses.…”

Section: Molecular Targetsmentioning

confidence: 99%

The dark side of the light: mechanisms of photocarcinogenesis

Coelho

Matos

Apetato

2016

Clinics in Dermatology

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Ultraviolet radiation (UVR) can have a beneficial biologic impact on skin, but it is also the most significant environmental risk factor for skin cancer development. Photocarcinogenesis comprises a complex interplay between the carcinogenic UVR, skin, and the immune system. UVB is absorbed by the superficial skin layers and is mainly responsible for direct DNA damage, which, if unrepaired, can lead to mutations in key cancer genes. UVA is less carcinogenic, penetrates deeper in the dermis, and mainly causes indirect oxidative damage to cellular DNA, proteins, and lipids, via photosensitized reactions. UVR not only induces mutagenesis, altering proliferation and differentiation of skin cells, but also has several immunosuppressive effects that compromise tumor immunosurveillance by impairing antigen presentation, inducing suppressive cells, and modulating the cytokine environment. This review focuses upon molecular and cellular effects of UVR, regarding its role in skin cancer development.

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“…5A). To better discriminate between the contribution of LCs and Ln + iDCs of the buccal mucosa, we used an approach that takes advantage of the differential repopulation kinetics of these DC subsets (41,42). Lang-DTR mice were treated with a single dose of DT 7 d before immunization (Fig.…”

Section: Different Function For Buccal and Lining Langerin + Dcs In Tmentioning

confidence: 99%

Dendritic Cells in Distinct Oral Mucosal Tissues Engage Different Mechanisms To Prime CD8+ T Cells

Nudel

Elnekave

Furmanov

et al. 2011

The Journal of Immunology

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Although oral dendritic cells (DCs) were shown to induce cell-mediated immunity, the identity and function of the various oral DC subsets involved in this process is unclear. In this study, we examined the mechanisms used by DCs of the buccal mucosa and of the lining mucosa to elicit immunity. After plasmid DNA immunization, buccally immunized mice generated robust local and systemic CD8+ T cell responses, whereas lower responses were seen by lining immunization. A delayed Ag presentation was monitored in vivo in both groups; yet, a more efficient presentation was mediated by buccal-derived DCs. Restricting transgene expression to CD11c+ cells resulted in diminished CD8+ T cell responses in both oral tissues, suggesting that immune induction is mediated mainly by cross-presentation. We then identified, in addition to the previously characterized Langerhans cells (LCs) and interstitial dendritic cells (iDCs), a third DC subset expressing the CD103+ molecule, which represents an uncharacterized subset of oral iDCs expressing the langerin receptor (Ln+iDCs). Using Langerin-DTR mice, we demonstrated that whereas LCs and Ln+iDCs were dispensable for T cell induction in lining-immunized mice, LCs were essential for optimal CD8+ T cell priming in the buccal mucosa. Buccal LCs, however, failed to directly present Ag to CD8+ T cells, an activity that was mediated by buccal iDCs and Ln+iDCs. Taken together, our findings suggest that the mechanisms engaged by oral DCs to prime T cells vary between oral mucosal tissues, thus emphasizing the complexity of the oral immune network. Furthermore, we found a novel regulatory role for buccal LCs in potentiating CD8+ T cell responses.

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Langerhans Cells Are Required for UVR-Induced Immunosuppression

Cited by 132 publications

References 57 publications

Glucocorticosteroids Modify Langerhans Cells To Produce TGF-β and Expand Regulatory T Cells

Glucocorticosteroids Modify Langerhans Cells To Produce TGF-β and Expand Regulatory T Cells

The dark side of the light: mechanisms of photocarcinogenesis

Dendritic Cells in Distinct Oral Mucosal Tissues Engage Different Mechanisms To Prime CD8+ T Cells

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