title: IL-27 Induces Th17 Differentiation in the Absence of STAT1 Signaling.
abstract: It is known that differentiation of Th17 cells is promoted by activation of STAT3 and inhibited by activation of STAT1. Although both transcription factors are activated by several cytokines, including IL-6, IL-21, and IL-27, each of these cytokines has a very different effect on Th17 differentiation, ranging from strong induction (IL-6) to strong inhibition (IL-27). To determine the molecular basis for these differences, we measured STAT3 and STAT1 activation profiles for IL-6, IL-21, and IL-27, as well as for cytokine pairs over time. We found that the ratio of activated STAT3/activated STAT1 is crucial in determining whether cytokines promote or inhibit Th17 differentiation. IL-6 and IL-21 induced p-STAT3/p-STAT1 ratios > 1, leading to the promotion of Th17 differentiation, whereas IL-27 or IL-6+IL-27 induced p-STAT3/p-STAT1 ratios < 1, resulting in inhibition of Th17 differentiation. Consistent with these findings, we show that IL-27 induces sufficient p-STAT3 to promote Th17 differentiation in the absence of STAT1. Furthermore, IL-27-induced STAT1-deficient T cells were indistinguishable from bona fide highly proinflammatory Th17 cells because they induced severe experimental autoimmune encephalomyelitis upon adoptive transfer. Our results suggest that the ratio of p-STAT3/p-STAT1 induced by a cytokine or cytokine pairs can be used to predict whether they induce a competent Th17-differentiation program.
authors.affiliation: Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors.forename: Anneli
authors.initials: A
authors.lastname: Peters
authors.affiliation: Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Fowler
authors.affiliation: Department of Pathology and Immunology, Geneva University Hospital, 1211 Geneva 4, Switzerland;
authors.forename: Fanny
authors.initials: F
authors.lastname: Chalmin
authors.affiliation: Department of Pathology and Immunology, Geneva University Hospital, 1211 Geneva 4, Switzerland; Department of Neuropathology, University Medical Center, 37075 Göttingen, Germany; and.
authors.forename: Doron
authors.initials: D
authors.lastname: Merkler
authors.affiliation: Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Caroline.Pot-Kreis@chuv.ch vkuchroo@evergrande.hms.harvard.edu.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.affiliation: Department of Pathology and Immunology, Geneva University Hospital, 1211 Geneva 4, Switzerland; Division of Neurology, Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland Caroline.Pot-Kreis@chuv.ch vkuchroo@evergrande.hms.harvard.edu.
authors.forename: Caroline
authors.initials: C
authors.lastname: Pot
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D064094:Interleukin-27 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D050794:STAT1 Transcription Factor / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects*; D000098546:Interleukin-21
chemical_list: D064094:Interleukin-27; D015850:Interleukin-6; D007378:Interleukins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D000098546:Interleukin-21