Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic TH17 cells

  • Nat Immunol. 2017 Jan;18(1):74-85. doi: 10.1038/ni.3632.
Sylvia Heink  1 ,  Nir Yogev  2 ,  Christoph Garbers  3 ,  Marina Herwerth  1  4 ,  Lilian Aly  1 ,  Christiane Gasperi  1 ,  Veronika Husterer  1 ,  Andrew L Croxford  2 ,  Katja Möller-Hackbarth  3 ,  Harald S Bartsch  5 ,  Karl Sotlar  5 ,  Stefan Krebs  6 ,  Tommy Regen  2 ,  Helmut Blum  6 ,  Bernhard Hemmer  1  7 ,  Thomas Misgeld  4  7 ,  Thomas F Wunderlich  8 ,  Juan Hidalgo  9 ,  Mohamed Oukka  10  11 ,  Stefan Rose-John  3 ,  Marc Schmidt-Supprian  12 ,  Ari Waisman  2 ,  Thomas Korn  1  7
Affiliations
  • 1. Klinikum rechts der Isar, Department of Neurology, Technical University of Munich, Munich, Germany.
  • 2. Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
  • 3. Institute of Biochemistry, Kiel University, Kiel, Germany.
  • 4. Institute of Neuronal Cell Biology, Technical University of Munich, Munich, Germany.
  • 5. Institute of Pathology, Medical School, Ludwig-Maximilians-University, Munich, Germany.
  • 6. Gene Centre, Lafuga, Ludwig-Maximilians-University, Munich, Germany.
  • 7. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
  • 8. Max Planck Institute for Metabolism Research, Cologne, Germany.
  • 9. Department of Cellular Biology, Physiology, and Immunology, Autonomous University of Barcelona, Barcelona, Spain.
  • 10. Department of Immunology, University of Washington, Seattle, Washington, USA.
  • 11. Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington, USA.
  • 12. Department of Hematology and Oncology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
PMID: 27893700 DOI: 10.1038/ni.3632
Abstract

The cellular sources of interleukin 6 (IL-6) that are relevant for differentiation of the TH17 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 TH17 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 TH17 cells in vivo. Our findings should guide therapeutic approaches for the treatment of TH17-cell-mediated autoimmune diseases.

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