Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Immunity. 2012 Apr 20;36(4):623-34. doi: 10.1016/j.immuni.2012.01.020. Epub 2012 Apr 12.
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.
白细胞介素 9（IL-9）是一种多功能细胞因子，可通过增强调节性 CD4（+）FoxP3（+）T 调节（Treg）细胞存活和辅助性 T 细胞 17（Th17）细胞增殖来调节自身免疫反应。在这里，我们分析了诱导 Th9 细胞的共刺激要求，并证明 Notch 途径与 TGF-β信号协同诱导 IL-9。Notch1 和 Notch2 受体的条件性缺失抑制了 Th9 细胞的发育。Notch1 细胞内结构域（NICD1）募集 TGF-β细胞因子信号下游的 Smad3，与 RBP-Jκ 一起结合 Il9 启动子并诱导其转录激活。在实验性自身免疫性脑脊髓炎（EAE）中，Jagged2 连接以依赖于 IL-9 的方式调节临床疾病。Jagged2 信号转导在抗原免疫之前给药时可扩张 Treg 细胞并抑制 EAE，但在免疫接种时给药会通过促进 Th17 细胞扩增而加重 EAE。我们提出 Notch 和 Smad3 合作诱导 IL-9 并参与调节免疫反应。
