Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic T_H17 cells

The cellular sources of interleukin 6 (IL-6) that are relevant for differentiation of the T_H17 subset of helper T cells remain unclear. Here we used a novel strategy for the conditional deletion of distinct IL-6-producing cell types to show that dendritic cells (DCs) positive for the signaling regulator Sirpα were essential for the generation of pathogenic T_H17 cells. Using their IL-6 receptor α-chain (IL-6Rα), Sirpα⁺ DCs trans-presented IL-6 to T cells during the process of cognate interaction. While ambient IL-6 was sufficient to suppress the induction of expression of the transcription factor Foxp3 in T cells, trans-presentation of IL-6 by DC-bound IL-6Rα (called 'IL-6 cluster signaling' here) was needed to prevent premature induction of interferon-γ (IFN-γ) expression in T cells and to generate pathogenic T_H17 cells in vivo. Our findings should guide therapeutic approaches for the treatment of T_H17-cell-mediated autoimmune diseases.