E‐cadherin interactions are required for Langerhans cell differentiation

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.