Abstract
Human skin contains the following two distinct DC subsets: (i) Langerhans cells (LCs), expressing Langerin but not DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), are predominantly localized in the epidermis; and (ii) dermal DCs, expressing DC-SIGN but not Langerin, are observed mainly in the dermis. It is not known whether localization in the epidermis provides cues for LC differentiation. Here, we show that E-cadherin expressed by epidermal keratinocytes (KCs) is crucial for differentiation of LCs. Monocytes differentiated into LC-like cells in presence of IL-4, GM-CSF, and TGF-β1. However, these LC-like cells expressed not only Langerin but also DC-SIGN. Notably, co-culturing of these LC-like cells with KCs expressing E-cadherin or recombinant E-cadherin strongly decreased expression of DC-SIGN and further induced a phenotype similar to purified epidermal LCs. Moreover, pretreatment of LC-like cells with anti-E-cadherin-specific antibody completely abolished their Langerin expression, indicating the requirement of E-cadherin–E-cadherin interactions for the differentiation into Langerin+ cells. These findings suggest that E-cadherin expressed by KCs provide environmental cues that induce differentiation of LCs in the epidermis.
Highlights
Skin and mucosal tissues contain two distinct DC subsets localized in distinct compartments
It has been reported that freshly isolated Langerhans cells (LCs) from the skin express both Langerin and E-cadherin, whereas E-cadherin is expressed by epidermal KCs [11]
E-cadherin was apparently induced on LClike cells when monocytes were cultured with TGF-β1 from the start of culture and the peak level was observed at 10 ng/mL (Fig. 2C)
Summary
Skin and mucosal tissues contain two distinct DC subsets localized in distinct compartments. Langerhans cells (LCs) are localized in the mucosal epithelial layer and epidermal layer in skin. These LCs are the first DC subset to encounter pathogens upon infection. In contrast to DCs, LCs have low or no expression of TLRs that recognize bacterial components such as TLR2 and TLR4 [6,7]. These data suggest that LCs might have a more tolerogenic function toward bacterial pathogens, their function remains unclear [8]
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