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

The cellular sources of interleukin 6 (IL-6) that are relevant for differentiation of the T sub(H)17 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 Sirp alpha were essential for the generation of pathogenic T sub(H)17 cells. Using their IL-6 receptor alpha -chain (IL-6R alpha ), Sirp alpha super(+) 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-6R alpha (called 'IL-6 cluster signaling' here) was needed to prevent premature induction of interferon- gamma (IFN- gamma ) expression in T cells and to generate pathogenic T sub(H)17 cells in vivo. Our findings should guide therapeutic approaches for the treatment of T sub(H)17-cell-mediated autoimmune diseases.