Interleukin 15 skews monocyte differentiation into dendritic cells with features of Langerhans cells

Langerhans cells (LCs) represent a subset of immature dendritic cells (DCs) specifically localized in the epidermis and other mucosal epithelia. As su rrounding keratinocytes can produce interleukin (IL)-15, a cytokine that ut ilizes IL-2R gamma chain, we analyzed whether IL-15 could skew monocyte dif ferentiation into LCs. Monocytes cultured for 6 d with granulocyte/macropha ge colony-stimulating factor (GM-CSF) and IL-15 differentiate into CD1a(+)H LA-DR(+)CD14(-)DCs (IL15-DCs). Agents such as lipopolysaccharide (LPS), tum or necrosis factor (TNF)alpha, and CD40L induce maturation of IL 15-DCs to CD83(+), DC-LAMP(+) cells. IL15-DCs are potent antigen-presenting cells abl e to induce the primary (mixed lymphocyte reaction [MLR]) and secondary (re call responses to flu-matrix peptide) immune responses. As opposed to cultu res made with GM-CSF/IL-4 (IL4-DCs), a proportion of IL15-DCs expresses LC markers: E-Cadherin, Langerin, and CC chemokine receptor (CCR)6. Accordingl y, IL15-DCs, but not IL4-DCs, migrate in response to macrophage inflammator y protein (MIP)-3 alpha /CCL20. However, IL15-DCs cannot be qualified as "g enuine" Langerhans cells because, despite the presence of the 43-kD Langeri n, they do not express bona fide Birbeck granules. Thus, our results demons trate a novel pathway in monocyte differentiation into dendritic cells.