title: Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic TH17 cells.
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.
authors.affiliation: Klinikum rechts der Isar, Department of Neurology, Technical University of Munich, Munich, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Heink
authors.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Nir
authors.initials: N
authors.lastname: Yogev
authors.affiliation: Institute of Biochemistry, Kiel University, Kiel, Germany.
authors.forename: Christoph
authors.identifier: 0000-0003-4939-6950
authors.initials: C
authors.lastname: Garbers
authors.affiliation: Klinikum rechts der Isar, Department of Neurology, Technical University of Munich, Munich, Germany.|Institute of Neuronal Cell Biology, Technical University of Munich, Munich, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Herwerth
authors.affiliation: Klinikum rechts der Isar, Department of Neurology, Technical University of Munich, Munich, Germany.
authors.forename: Lilian
authors.identifier: 0000-0002-7051-124X
authors.initials: L
authors.lastname: Aly
authors.affiliation: Klinikum rechts der Isar, Department of Neurology, Technical University of Munich, Munich, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Gasperi
authors.affiliation: Klinikum rechts der Isar, Department of Neurology, Technical University of Munich, Munich, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Husterer
authors.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Croxford
authors.affiliation: Institute of Biochemistry, Kiel University, Kiel, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Möller-Hackbarth
authors.affiliation: Institute of Pathology, Medical School, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Harald S
authors.initials: HS
authors.lastname: Bartsch
authors.affiliation: Institute of Pathology, Medical School, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Sotlar
authors.affiliation: Gene Centre, Lafuga, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Krebs
authors.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Tommy
authors.initials: T
authors.lastname: Regen
authors.affiliation: Gene Centre, Lafuga, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Blum
authors.affiliation: Klinikum rechts der Isar, Department of Neurology, Technical University of Munich, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hemmer
authors.affiliation: Institute of Neuronal Cell Biology, Technical University of Munich, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Misgeld
authors.affiliation: Max Planck Institute for Metabolism Research, Cologne, Germany.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Wunderlich
authors.affiliation: Department of Cellular Biology, Physiology, and Immunology, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Hidalgo
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, USA.|Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Oukka
authors.affiliation: Institute of Biochemistry, Kiel University, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Department of Hematology and Oncology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Schmidt-Supprian
authors.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Ari
authors.identifier: 0000-0003-4304-8234
authors.initials: A
authors.lastname: Waisman
authors.affiliation: Klinikum rechts der Isar, Department of Neurology, Technical University of Munich, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Korn
mesh_terms: D000818:Animals; D015551:Autoimmunity; D002454:Cell Differentiation; D002478:Cells, Cultured; D002490:Central Nervous System / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D053698:Interleukin-6 Receptor alpha Subunit / Q000235:genetics*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015850:Interleukin-6; D053698:Interleukin-6 Receptor alpha Subunit; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic; C445081:myelin oligodendrocyte glycoprotein (35-55)