Trans-presentation of interleukin-6 by dendritic cells is required for priming pathogenic T(H)17 cells

The cellular sources of interleukin-6 (IL-6) that are relevant for the differentiation of T(H)17 cells remain unclear. Here, we used a novel strategy of IL-6 conditional deletion of distinct IL-6-producing cell types to show that Sirpα(+) dendritic cells (DC) were essential for the generation of pathogenic T(H)17 cells. During the process of cognate interaction, Sirpα(+) DCs trans-presented IL-6 to T cells using their own IL-6Rα. While ambient IL-6 was sufficient to suppress the induction of the transcription factor Foxp3 in T cells, IL-6 trans-presentation by DC-bound IL-6Rα (here defined as IL-6 cluster signaling) was required to prevent premature induction of IFN-γ in T cells and to generate pathogenic T(H)17 cells in vivo. These findings will guide therapeutic approaches for T(H)17-mediated autoimmune diseases.