title: IL-27 and IL-12 oppose pro-inflammatory IL-23 in CD4+ T cells by inducing Blimp1.
abstract: Central nervous system (CNS) autoimmunity is regulated by the balance of pro-inflammatory cytokines and IL-10. Here we identify the transcriptional regulator Blimp1 as crucial to induce IL-10 in inflammatory T helper cells. Pre-committed Th17 cells respond to IL-27 and IL-12 by upregulating Blimp1 and adopt a Tr-1-like phenotype characterized by IL-10 and IFN-γ production. Accordingly, Blimp1-deficient effector T cells fail to produce IL-10, and deficiency in Tr-1 cell function leads to uncontrolled Th17 cell-driven CNS pathology without the need to stabilize the Th17 phenotype with IL-23. IL-23 counteracts IL-27 and IL-12-mediated effects on Tr-1-development reinforcing the pro-inflammatory phenotype of Th17 cells. Thus, the balance of IL-23 vs IL-12/IL-27 signals into CD4(+) effector T cells determines whether tissue inflammation is perpetuated or resolves.
authors.affiliation: 1] Klinikum rechts der Isar, Department of Neurology, Technische Universität München, Ismaninger Straße 22, 81675 Munich, Germany [2].
authors.forename: Christina
authors.initials: C
authors.lastname: Heinemann
authors.affiliation: 1] Klinikum rechts der Isar, Department of Neurology, Technische Universität München, Ismaninger Straße 22, 81675 Munich, Germany [2].
authors.forename: Sylvia
authors.initials: S
authors.lastname: Heink
authors.affiliation: Klinikum rechts der Isar, Department of Neurology, Technische Universität München, Ismaninger Straße 22, 81675 Munich, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Petermann
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Ajithkumar
authors.initials: A
authors.lastname: Vasanthakumar
authors.affiliation: Klinikum rechts der Isar, Department of Neurology, Technische Universität München, Ismaninger Straße 22, 81675 Munich, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Rothhammer
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Elien
authors.initials: E
authors.lastname: Doorduijn
authors.affiliation: Klinikum rechts der Isar, Department of Neurology, Technische Universität München, Ismaninger Straße 22, 81675 Munich, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Mitsdoerffer
authors.affiliation: Klinikum rechts der Isar, Department of Neurology, Technische Universität München, Ismaninger Straße 22, 81675 Munich, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Sie
authors.affiliation: Institute for Medical Microbiology, Immunology, and Hygiene, Technische Universität München, Trogerstraße 30, 81675 Munich, Germany.
authors.forename: Olivia
authors.initials: O
authors.lastname: Prazeres da Costa
authors.affiliation: Institute for Medical Microbiology, Immunology, and Hygiene, Technische Universität München, Trogerstraße 30, 81675 Munich, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Buch
authors.affiliation: 1] Klinikum rechts der Isar, Department of Neurology, Technische Universität München, Ismaninger Straße 22, 81675 Munich, Germany [2] Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hemmer
authors.affiliation: Seattle Children's Hospital, Center for Immunity and Immunotherapies, University of Washington School of Medicine, 1900 Ninth Avenue, M/S C9S-7, Seattle, Washington 98101, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Oukka
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Axel
authors.initials: A
authors.lastname: Kallies
authors.affiliation: 1] Klinikum rechts der Isar, Department of Neurology, Technische Universität München, Ismaninger Straße 22, 81675 Munich, Germany [2] Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Korn
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000517:prevention & control*; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism*; D053759:Interleukin-23 / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: D053759:Interleukin-23; D007378:Interleukins; C464565:MYDGF protein, human; D012097:Repressor Proteins; C087042:PRDM1 protein, human; D018664:Interleukin-12; D007371:Interferon-gamma; D000074462:Positive Regulatory Domain I-Binding Factor 1