Notch Receptors and Smad3 Signaling Cooperate in the Induction of Interleukin-9-Producing T Cells

SummaryInterleukin 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.

► Notch1 and Notch2 receptors are required for the differentiation of Th9 cells ► Jagged2 but not Delta-like1 convert naive T cells into pre-Th9 cells ► NICD binds to Smad3 in Th9 cells and together transactivate the Il9 promoter ► The timing of IL-9 signal and the cytokine milieu in EAE determine the outcome of clinical disease