Distinct subsets of human skin dendritic cells differ on their ability to initiate Th17 responses (90.24)

Abstract

Abstract Activated human cutaneous dendritic cells (DCs) have the ability to initiate Th1 and Th2 immunity. However, whether human cutaneous DCs are capable of biasing pro-inflammatory Th17 responses remains little understood. Utilizing human skin explants composed by both epidermis and dermis or epidermal or dermal sheets to collect activated skin-migratory DCs (smiDCs), we demonstrated that smiDCs stimulate allogeneic naïve CD4+ T cells to differentiate simultaneously into two distinct effector Th17 and Th1 populations with ability of skin homing and inducing severe tissue damage. Of the two main myeloid DC populations resident in the skin, the subset of epidermal skin-migratory Langerhans cells (smiLCs) were capable of inducing Th17 responses. This effect depended on the combined effects of IL-15 and stabilized IL-6 trans-signaling of naïve CD4+ T cells. Purified skin-migratory DDCs did not synthesize IL-15 and were unable to bias Th17 responses however, they acquired the ability to bias Th17 cells in co-cultures with CD4+ T cells supplemented with IL-15 and stabilized IL-6. Overall, our data demonstrate that human cutaneous LCs induce Th17 responses by mechanisms different from those previously described for mouse DCs and human monocytes and highlight the need to target clinical treatments based on these variations. Supported by NIH grants: R01 CA100893 (ATL)