title: BCL6 controls Th9 cell development by repressing Il9 transcription.
abstract: The transcriptional repressor B cell lymphoma 6 (BCL6) is required for the development of Th follicular cells, and it has been shown to suppress Th2 cell differentiation. We demonstrate that BCL6 is a key regulator of Th9 cell development. BCL6 expression is transiently downregulated in polarized Th9 cells, and forced expression of BCL6 in Th9 cells impairs Th9 cell differentiation. In contrast, BCL6 knockdown upregulated IL-9 production in Th9 cells. The function of BCL6 in Th9 cells is under the control of IL-2/JAK3/STAT5 signaling pathway. Using chromatin immunoprecipitation, we show that, in Th9 cells, BCL6 and STAT5 bind to adjacent motifs in the Il9 promoter. Furthermore, we found that STAT5 binding was associated with the abundance of a permissive histone mark at the Il9 promoter, whereas under conditions in which BCL6 binding was predominant, a repressive histone mark was prevalent. The effects of STAT5 and BCL6 on IL-9 transcription were further demonstrated using an IL-9 luciferase reporter assay in which BCL6 repressed STAT5-mediated Il9 transactivation. In experimental autoimmune encephalomyelitis, forced expression of BCL6 in myelin oligodendrocyte glycoprotein35-55-specific Th9 cells resulted in decreased IL-9 production and induction of IFN-γ, causing an exacerbation of the clinical disease. Our findings demonstrate a novel role of BCL6 in the regulation of Th9 cell development and their encephalitogenicity.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; and.
authors.forename: Ribal
authors.initials: R
authors.lastname: Bassil
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; and.
authors.forename: William
authors.initials: W
authors.lastname: Orent
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; and.
authors.forename: Marta
authors.initials: M
authors.lastname: Olah
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; and.
authors.forename: Ahmed T
authors.initials: AT
authors.lastname: Kurdi
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Frangieh
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Buttrick
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; and Abu Haidar Neuroscience Institute, American University of Beirut, Beirut 1107-2020, Lebanon welyaman@rics.bwh.harvard.edu skhoury@rics.bwh.harvard.edu.
authors.forename: Samia J
authors.initials: SJ
authors.lastname: Khoury
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; and welyaman@rics.bwh.harvard.edu skhoury@rics.bwh.harvard.edu.
authors.forename: Wassim
authors.initials: W
authors.lastname: Elyaman
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D016906:Interleukin-9 / Q000235:genetics / Q000276:immunology*; D053616:Janus Kinase 3 / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D051560:Proto-Oncogene Proteins c-bcl-6; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000473:pathology; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology*; D015533:Transcriptional Activation / Q000235:genetics / Q000276:immunology*
chemical_list: C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D016906:Interleukin-9; D051560:Proto-Oncogene Proteins c-bcl-6; D050799:STAT5 Transcription Factor; D007371:Interferon-gamma; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3