• A Corrigendum to this article was published on 22 March 2017

This article has been updated

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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Change history

  • 23 January 2017

    In the version of this article initially published, the label for third bar from the left in Figure 4f ('Anti-IL-6α') was incorrect; the correct label is 'Anti-IL-6Rα'. Also, in the legend for Figure 4f, the description of the treatment conditions for middle four bars ('medium alone, or LPS and anti-IL-6 (MR16-1 or polyclonal antibody), anti-IL-6R (mAb#8)') was incorrect; the correct description is 'LPS alone (Medium), or LPS and anti-IL-6Rα (MR16-1), anti-IL-6 (polyclonal antibody or mAb#8)'. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank all members of the Korn laboratory for input; B. Kunze, B. Lunk and colleagues for mouse care; D. Busch (Technical University of Munich) for OT-II mice (Tg(TcraTcrb)425Cbn) expressing the congenic marker CD45.1; F. Greten (Georg-Speyer Haus) for Stat3flox/flox (Stat3tm2Aki) mice; B. Stockinger (MRC National Institute for Medical Research) for the 19E12 hybridoma; and M. Kopf (ETH, Zürich) for Il21r−/− mice. Supported by the Deutsche Forschungsgemeinschaft (TRR128 to A.W. and T.K.; TRR156 and WA1600/8-1 to A.W.; SFB1054-B07 and SyNergy to T.K.; SFB877-A01 to S.R.-J.; SFB877-A10 to C. Gar.; and the cluster of excellence 'Inflammation at interfaces' to S.R.-J. and C. Gar.), the European Research Council (Consolidator Grant 647215 to T.K.), and the Spanish Ministerio de Economía y Competitividad (SAF2011-23272 and SAF2014-56546-R to J.H.).

Author information

Author notes

    • Nir Yogev

    Present address: Department of Neurology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

    • Sylvia Heink
    •  & Nir Yogev

    These authors contributed equally to this work.

    • Ari Waisman
    •  & Thomas Korn

    These authors jointly directed this work.

Affiliations

  1. Klinikum rechts der Isar, Department of Neurology, Technical University of Munich, Munich, Germany.

    • Sylvia Heink
    • , Marina Herwerth
    • , Lilian Aly
    • , Christiane Gasperi
    • , Veronika Husterer
    • , Bernhard Hemmer
    •  & Thomas Korn
  2. Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

    • Nir Yogev
    • , Andrew L Croxford
    • , Tommy Regen
    •  & Ari Waisman
  3. Institute of Biochemistry, Kiel University, Kiel, Germany.

    • Christoph Garbers
    • , Katja Möller-Hackbarth
    •  & Stefan Rose-John
  4. Institute of Neuronal Cell Biology, Technical University of Munich, Munich, Germany.

    • Marina Herwerth
    •  & Thomas Misgeld
  5. Institute of Pathology, Medical School, Ludwig-Maximilians-University, Munich, Germany.

    • Harald S Bartsch
    •  & Karl Sotlar
  6. Gene Centre, Lafuga, Ludwig-Maximilians-University, Munich, Germany.

    • Stefan Krebs
    •  & Helmut Blum
  7. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

    • Bernhard Hemmer
    • , Thomas Misgeld
    •  & Thomas Korn
  8. Max Planck Institute for Metabolism Research, Cologne, Germany.

    • Thomas F Wunderlich
  9. Department of Cellular Biology, Physiology, and Immunology, Autonomous University of Barcelona, Barcelona, Spain.

    • Juan Hidalgo
  10. Department of Immunology, University of Washington, Seattle, Washington, USA.

    • Mohamed Oukka
  11. Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington, USA.

    • Mohamed Oukka
  12. Department of Hematology and Oncology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

    • Marc Schmidt-Supprian

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Contributions

S.H. designed, performed and analyzed most experiments and drafted the manuscript; N.Y. performed and analyzed key in vivo experiments; C. Gar., M.H., L.A., V.H., A.L.C., K.M.-H. and T.R. performed or contributed to specific experiments; C.Gas. performed bioinformatics analysis; H.S.B. and K.S. performed and analyzed nanostring experiments; S.K. and H.B. performed and analyzed RNA-sequencing experiments; B.H., T.M., T.F.W., J.H., M.O., S.R.-J., M.S.-S. provided reagents, advice, design and supervision of experiments; A.W. supervised experiments, analyzed data and wrote the manuscript; and T.K. conceptualized the study, designed and supervised the experiments, analyzed data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Thomas Korn.

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DOI

https://doi.org/10.1038/ni.3632

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