Abstract
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 TGFβ. Ιn vitro, LC can be generated from monocytes in the presence of GM-CSF, IL-4 and TGFβ. However, the signals that induce LC during an inflammatory reaction are not fully investigated. Here we report that Activin A, a TGFβ family member induced by pro-inflammatory cytokines and involved in skin morphogenesis and wound healing, induces the differentiation of human monocytes into LC in the absence of TGFβ. 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 TGFβ, responsible for LC differentiation during inflammatory/autoimmune conditions.
Highlights
Langerhans cells (LC) are specialized dendritic cells (DC) normally found in the epidermis and mucosal stratified epithelia [1,2,3,4,5]
Purified monocytes were cultured for 6 days with Activin A in the presence of GM-CSF and IL-4, two cytokines that were shown to cooperate with TGFb1 in the differentiation of monocytes to LC [16; 18]
These cells were CD142 and expressed typical LC markers, such as CD1a, Langerin, E-caderin, cutaneous lymphocyte-associated antigen (CLA) and chemokine receptor 6 (CCR6)
Summary
Langerhans cells (LC) are specialized dendritic cells (DC) normally found in the epidermis and mucosal stratified epithelia [1,2,3,4,5]. LC express a characteristic set of cell-surface molecules, such as cutaneous lymphocyte-associated antigen (CLA), E-cadherin and the CC chemokine receptor 6 (CCR6) [9,10,11,12,13]. As immature cells, their primary function is to sense the environment for danger signals and capture antigens; LC undergo a process of functional and phenotypic maturation and migrate to the regional lymph nodes [5; 10; 14; 15]. IL-15 is the only other cytokine known until now to skew monocyte differentiation toward LC-type DC; though, IL-15-derived LC are Langerin+ but lack Birbeck granules [22]
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