Langerhans cells are negative regulators of the anti-<i>Leishmania</i> response

Kautz-Neu, Kordula; Noordegraaf, Mirko; Dinges, Stephanie; Bennett, Clare L.; John, Dominik; Clausen, Björn E.; Stebut, Esther von

doi:10.1084/jem.20102318

Cited by 150 publications

(129 citation statements)

References 30 publications

(52 reference statements)

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“…The in vivo function of LCs is somewhat enigmatic. In vivo, LCs suppress adaptive responses to hapten and Leishmania skin infection (16,31). They are required for the generation Th17 responses to C. albicans and may participate in local activation of cytotoxic T lymphocytes (CTL) in graft-vs.-host disease (24,32).…”

Section: Discussionmentioning

confidence: 99%

Autocrine/paracrine TGF-β1 inhibits Langerhans cell migration

Bobr

Igyártó

Haley

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Langerhans cells (LCs) are skin-resident dendritic cells (DC) located in the epidermis that migrate to skin-draining lymph nodes during the steady state and in response to inflammatory stimuli. TGF-β1 is a critical immune regulator that is highly expressed by LCs. The ability to test the functional importance of LC-derived TGF-β1 is complicated by the requirement of TGF-β1 for LC development and by the absence of LCs in mice with an LC-specific ablation of TGF-β1 or its receptor. To overcome these problems, we have engineered transgenic huLangerin-CreER T2 mice that allow for inducible LC-specific excision. Highly efficient and LC-specific expression was confirmed in mice bred onto a YFP Cre reporter strain. We next generated huLangerin-CreER T2 × TGF-βRII fl and huLangerin-CreER T2 × TGF-β1 fl mice. Excision of the TGFβRII or TGFβ1 genes induced mass migration of LCs to the regional lymph node. Expression of costimulatory markers and inflammatory cytokines was unaffected, consistent with homeostatic migration. In addition, levels of p-SMAD2/3 were decreased in LCs from wild-type mice before inflammation-induced migration. We conclude that TGF-β1 acts directly on LCs in an autocrine/paracrine manner to inhibit steady-state and inflammationinduced migration. This is a readily targetable pathway with potential therapeutic implications for skin disease.skin immunology | pSMAD2/3 | tolerance

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Section: Discussionmentioning

confidence: 99%

Autocrine/paracrine TGF-β1 inhibits Langerhans cell migration

Bobr

Igyártó

Haley

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Langerhans cells (LCs) reside in the epidermis and are characterized by expression of Langerin/CD207, which they share with a small population of Langerin + cDCs in the dermis, whereas the majority of dermal cDCs are Langerin neg . Recent observations indicate a functional specialization of the different skin-resident cDC subsets and, in particular, LCs can exert regulatory functions (e.g., during Leishmania major infection), whereas dermal cDCs may be more immunogenic (12,13). In this study, we sought to dissect whether and how the different skin DC populations promote or regulate psoriatic plaque formation.…”

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confidence: 99%

Langerin ^neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

Wohn

Ober‐Blöbaum

Haak

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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169

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Psoriasis is an autoinflammatory skin disease of unknown etiology. Topical application of Aldara cream containing the Toll-like receptor (TLR)7 agonist Imiquimod (IMQ) onto patients induces flares of psoriasis. Likewise, in mice IMQ triggers pathological changes closely resembling psoriatic plaque formation. Key cytokines like IL-23 and type-I IFN (IFN-I), both being produced mainly by dendritic cells (DCs), have been implicated in psoriasis. Although plasmacytoid DCs (pDCs) are the main source of IFNα and thought to initiate disease, conventional DCs (cDCs) appear to maintain the psoriatic lesions. Any role of cDCs during lesion formation remains elusive. Here, we report that selective activation of TLR7 signaling specifically in CD11c + DCs was sufficient to induce psoriasiform skin disease in mice. Intriguingly, both pDCs and the IFN-I pathway were dispensable for the development of local skin inflammation. Selective TLR7 triggering of Langerin + DCs resulted in attenuated disease, whereas their depletion did not alter the severity of skin lesions. Moreover, after IMQ-painting, IL-23 was exclusively produced by Langerin neg DCs in vivo. In conclusion, TLR7-activated Langerin neg cDCs trigger psoriatic plaque formation via IL-23-mediated activation of innate IL-17/IL-22-producing lymphocytes, independently of pDCs or IFN-I. These results suggest therapeutic targeting of IL-23 production by cDCs to refine current treatment strategies for psoriasis.

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“…It was shown that LCs can prime CD4 + Th17 cells under inflammatory conditions, as well as Th2 responses via thymic stromal lymphopoietin signaling (3,4). LCs also can limit adaptive immune responses by stimulating the differentiation of T regulatory cells (5)(6)(7). In contrast to CD4 + T cells, LCs were shown to be dispensable for CD8 + T cell priming in numerous experimental systems (8)(9)(10)(11).…”

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confidence: 99%

Second-Generation Langerhans Cells Originating from Epidermal Precursors Are Essential for CD8+ T Cell Priming

Elnekave

Furmanov

Shaul

et al. 2014

The Journal of Immunology

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In vivo studies questioned the ability of Langerhans cells (LCs) to mediate CD8+ T cell priming. To address this issue, we used intradermal immunization with plasmid DNA, a system in which activation of CD8+ T cells depends on delayed kinetics of Ag presentation. We found that dendritic cells (DCs) located in the skin at the time of immunization have limited ability to activate CD8+ T cells. This activity was mediated by a second generation of DCs that differentiated in the skin several days after immunization, as well as by lymph node–resident DCs. Intriguingly, CD8+ T cell responses were not affected following treatment with clodronate liposomes, immunization of CCR2−/− mice, or local neutralization of CCL20. This suggests that local, rather than blood-derived, DC precursors mediate CD8+ T cell priming. Analysis of DC differentiation in the immunized skin revealed a gradual increase in the number of CD11c+ cells, which reached their maximum 2 wk after immunization. A similar differentiation kinetics was observed for LCs, with the majority of differentiating LCs proliferating in situ from epidermal precursors. By using B6/Langerin–diphtheria toxin receptor chimeric mice and LC ablation, we demonstrated that epidermal LCs were crucial for the elicitation of CD8+ T cell responses in vivo. Furthermore, LCs isolated from lymph nodes 2 wk after immunization contained the immunization plasmid and directly activated Ag-specific CD8+ T cells ex vivo. Thus, these results indicate that second-generation Ag-expressing LCs differentiating from epidermal precursors directly prime CD8+ T cells and are essential for optimal cellular immune responses following immunization with plasmid DNA.

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Langerhans cells are negative regulators of the anti-Leishmania response

Abstract: Langerhans cells suppress the immune response to low-dose Leishmania major infection in part by inducing regulatory T cells.

Cited by 150 publications

References 30 publications

Autocrine/paracrine TGF-β1 inhibits Langerhans cell migration

Autocrine/paracrine TGF-β1 inhibits Langerhans cell migration

Langerin ^neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

Second-Generation Langerhans Cells Originating from Epidermal Precursors Are Essential for CD8+ T Cell Priming

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Langerhans cells are negative regulators of the anti-Leishmania response

Abstract: Langerhans cells suppress the immune response to low-dose Leishmania major infection in part by inducing regulatory T cells.

Cited by 150 publications

References 30 publications

Autocrine/paracrine TGF-β1 inhibits Langerhans cell migration

Autocrine/paracrine TGF-β1 inhibits Langerhans cell migration

Langerin neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

Second-Generation Langerhans Cells Originating from Epidermal Precursors Are Essential for CD8+ T Cell Priming

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Langerin ^neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice