Activin A Induces Langerhans Cell Differentiation In Vitro and in Human Skin Explants

Langerhans cells (LC) represent a well characterized subset of dendritic cells located in the epidermis of skin and mucosae. In vivo, they originate from resident and blood-borne precursors in the presence of keratinocyte-derived TGF beta. In vitro, LC can be generated from monocytes in the presence of GM-CSF, IL-4 and TGF beta. However, the signals that induce LC during an inflammatory reaction are not fully investigated. Here we report that Activin A, a TGF beta family member induced by proinflammatory cytokines and involved in skin morphogenesis and wound healing, induces the differentiation of human monocytes into LC in the absence of TGF beta. Activin A-induced LC are Langerin(+), Birbeck granules(+), E-cadherin(+), CLA(+) and CCR6(+) and possess typical APC functions. In human skin explants, intradermal injection of Activin A increased the number of CD1a(+) and Langerin(+) cells in both the epidermis and dermis by promoting the differentiation of resident precursor cells. High levels of Activin A were present in the upper epidermal layers and in the dermis of Lichen Planus biopsies in association with a marked infiltration of CD1a(+) and Langerin(+) cells. This study reports that Activin A induces the differentiation of circulating CD14(+) cells into LC. Since Activin A is abundantly produced during inflammatory conditions which are also characterized by increased numbers of LC, we propose that this cytokine represents a new pathway, alternative to TGF beta, responsible for LC differentiation during inflammatory/autoimmune conditions.