Ginhoux F, Collin MP, Bogunovic M, Abel M, Leboeuf M, Helft J et al.Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state. J Exp Med 204:3133-3146

Department of Gene and Cell Medicine, Mount Sinai School of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 01/2008; 204(13):3133-46. DOI: 10.1084/jem.20071733
Source: PubMed

ABSTRACT Langerin is a C-type lectin receptor that recognizes glycosylated patterns on pathogens. Langerin is used to identify human and mouse epidermal Langerhans cells (LCs), as well as migratory LCs in the dermis and the skin draining lymph nodes (DLNs). Using a mouse model that allows conditional ablation of langerin(+) cells in vivo, together with congenic bone marrow chimeras and parabiotic mice as tools to differentiate LC- and blood-derived dendritic cells (DCs), we have revisited the origin of langerin(+) DCs in the skin DLNs. Our results show that in contrast to the current view, langerin(+)CD8(-) DCs in the skin DLNs do not derive exclusively from migratory LCs, but also include blood-borne langerin(+) DCs that transit through the dermis before reaching the DLN. The recruitment of circulating langerin(+) DCs to the skin is dependent on endothelial selectins and CCR2, whereas their recruitment to the skin DLNs requires CCR7 and is independent of CD62L. We also show that circulating langerin(+) DCs patrol the dermis in the steady state and migrate to the skin DLNs charged with skin antigens. We propose that this is an important and previously unappreciated element of immunosurveillance that needs to be taken into account in the design of novel vaccine strategies.

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    • "A recent study showed that LCs activate skin-resident regulatory T cells and maintain skin homeostasis11. Langerin+CD103+ DDCs play a role in antigen cross-presentation121314, whereas CD103−DDCs are responsible for the transport of invading pathogens to the dLN151617. For example, CD103−DDCs have been reported to transfer antigen to CD8α+ LN-resident DCs after herpes simplex virus infection of the skin3. "
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    ABSTRACT: Skin-derived dendritic cells (DCs) play a crucial role in the maintenance of immune homeostasis due to their role in antigen trafficking from the skin to the draining lymph nodes (dLNs). To quantify the spatiotemporal regulation of skin-derived DCs in vivo, we generated knock-in mice expressing the photoconvertible fluorescent protein KikGR. By exposing the skin or dLN of these mice to violet light, we were able to label and track the migration and turnover of endogenous skin-derived DCs. Langerhans cells and CD103(+)DCs, including Langerin(+)CD103(+)dermal DCs (DDCs), remained in the dLN for 4-4.5 days after migration from the skin, while CD103(-)DDCs persisted for only two days. Application of a skin irritant (chemical stress) induced a transient >10-fold increase in CD103(-)DDC migration from the skin to the dLN. Tape stripping (mechanical injury) induced a long-lasting four-fold increase in CD103(-)DDC migration to the dLN and accelerated the trafficking of exogenous protein antigens by these cells. Both stresses increased the turnover of CD103(-)DDCs within the dLN, causing these cells to die within one day of arrival. Therefore, CD103(-)DDCs act as sentinels against skin invasion that respond with increased cellular migration and antigen trafficking from the skin to the dLNs.
    Scientific Reports 08/2014; 4:6030. DOI:10.1038/srep06030 · 5.58 Impact Factor
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    • "ACD is one of the most common skin diseases caused by complex immune mechanisms in response to a variety of reactive contact sensitizers, such as metals, preservatives and hair dyes, and is well-modelled by CHS in mice. In the sensitization phase of CHS, epidermal proteins cross-linked with applied haptens are acquired mainly by two populations of dendritic cells (DCs), epidermal Langerhans cells (LCs) and Langerin-positive dermal DCs (dDCs), which have been shown to function redundantly34567. These DCs migrate to the draining lymph nodes (LNs), where they prime hapten-specific effector T cells. "
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    ABSTRACT: Contact hypersensitivity (CHS) is a form of delayed-type hypersensitivity triggered by the response to reactive haptens (sensitization) and subsequent challenge (elicitation). Here, we show that ASK1 promotes CHS and that suppression of ASK1 during the elicitation phase is sufficient to attenuate CHS. ASK1 knockout (KO) mice exhibited impaired 2,4-dinitrofluorobenzene (DNFB)-induced CHS. The suppression of ASK1 activity during the elicitation phase through a chemical genetic approach or a specific inhibitory compound significantly reduced the CHS response to a level similar to that observed in ASK1 KO mice. The reduced response was concomitant with the strong inhibition of production of IL-17, a cytokine that plays an important role in CHS and other inflammatory diseases, from sensitized lymph node cells. These results suggest that ASK1 is relevant to the overall CHS response during the elicitation phase and that ASK1 may be a promising therapeutic target for allergic contact dermatitis and other IL-17-related inflammatory diseases.
    Scientific Reports 04/2014; 4:4714. DOI:10.1038/srep04714 · 5.58 Impact Factor
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    • "It is possible that LC tolerogenicity depends on maturation state (reviewed in [37]), as immature LC can migrate to draining LN [38]. Also, as LC were not distinguished from Lang+ dermal DC in many earlier studies, Lang+ dermal DC may cause the tolerogenic effects currently ascribed to LC [11], [39], reviewed in [37]. "
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    ABSTRACT: Topical antigen application is a focus of current vaccine research. This immunization route mimics natural antigen exposure across a barrier tissue and generates T cells imprinted for skin-selective homing. Soluble antigens introduced through this route require cross-presentation by DC to generate CD8 T cell responses. Here we have explored the relative contribution of various skin-derived DC subsets to cross-priming and skin-selective imprinting. In our model, DC acquire soluble Ag in vivo from immunized murine skin for cross-presentation to naïve CD8 T cells ex vivo. We find CD11b+ migratory DC to be the relevant cross-priming DC in this model. Both Langerin+ and Langerin- CD11b+ migratory DC can cross-present antigen in our system, but only the Langerin+ subset can induce expression of the skin-selective addressin E-selectin ligand. Thus, the CD11b+ Langerin+ migratory DC population, comprised primarily of Langerhans cells, both cross-primes naïve CD8 T cells and imprints them with skin-homing capabilities.
    PLoS ONE 03/2014; 9(3):e91054. DOI:10.1371/journal.pone.0091054 · 3.23 Impact Factor
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