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Heink, Sylvia; Yogev, Nir; Garbers, Christoph; Herwerth, Marina; Aly, Lilian; Gasperi, Christiane; Husterer, Veronika; Croxford, Andrew L.; Möller-Hackbarth, Katja; Bartsch, Harald S.; Sotlar, Karl; Krebs, Stefan; Regen, Tommy; Blum, Helmut; Hemmer, Bernhard; Misgeld, Thomas; Wunderlich, Thomas F.; Hidalgo, Juan; Oulcka, Mohamed; Rose-John, Stefan; Schmidt-Supprian, Marc; Waisman, Ari; Korn, Thomas (2017): Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic T(H)17 cells. In: Nature Immunology, Vol. 18, No. 1: pp. 74-85
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The cellular sources of interleukin 6 (IL-6) that are relevant for differentiation of the T(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(H)17 cells. Using their IL-6 receptor a-chain (IL-6R alpha), Sirp alpha(+) 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(H)17 cells in vivo. Our findings should guide therapeutic approaches for the treatment of T(H)17-cell-mediated autoimmune diseases.