title: Notch receptors and Smad3 signaling cooperate in the induction of interleukin-9-producing T cells.
abstract: Interleukin 9 (IL-9) is a pleiotropic cytokine that can regulate autoimmune responses by enhancing regulatory CD4(+)FoxP3(+) T regulatory (Treg) cell survival and T helper 17 (Th17) cell proliferation. Here, we analyzed the costimulatory requirements for the induction of Th9 cells, and demonstrated that Notch pathway cooperated with TGF-β signaling to induce IL-9. Conditional ablation of Notch1 and Notch2 receptors inhibited the development of Th9 cells. Notch1 intracellular domain (NICD1) recruited Smad3, downstream of TGF-β cytokine signaling, and together with recombining binding protein (RBP)-Jκ bound the Il9 promoter and induced its transactivation. In experimental autoimmune encephalomyelitis (EAE), Jagged2 ligation regulated clinical disease in an IL-9-dependent fashion. Signaling through Jagged2 expanded Treg cells and suppressed EAE when administered before antigen immunization, but worsened EAE when administered concurrently with immunization by favoring Th17 cell expansion. We propose that Notch and Smad3 cooperate to induce IL-9 and participate in regulating the immune response.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Wassim
authors.initials: W
authors.lastname: Elyaman
authors.forename: Ribal
authors.initials: R
authors.lastname: Bassil
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Bradshaw
authors.forename: William
authors.initials: W
authors.lastname: Orent
authors.forename: Youmna
authors.initials: Y
authors.lastname: Lahoud
authors.forename: Bing
authors.initials: B
authors.lastname: Zhu
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Samia J
authors.initials: SJ
authors.lastname: Khoury
mesh_terms: D000818:Animals; D002450:Cell Communication; D002454:Cell Differentiation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D005260:Female; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D016906:Interleukin-9 / Q000096:biosynthesis / Q000378:metabolism*; D000072101:Jagged-2 Protein; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism*; D053651:Receptors, Interleukin-9 / Q000235:genetics; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta
chemical_list: C508448:Il9r protein, mouse; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D016906:Interleukin-9; C490503:Jag2 protein, mouse; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; C497571:Rbpj protein, mouse; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D053651:Receptors, Interleukin-9; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta