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. 2018 Aug 14;9:1823. doi: 10.3389/fimmu.2018.01823

Figure 4.

Figure 4

The interaction between Notch and interleukin 17 (IL-17) in different immune cellular settings. (A) Notch signaling stimulates Th17 cell differentiation. 1. Dll4, upregulated on DC cells upon TLR activation, in cooperation with skewing cytokines, IL-6 and transforming growth factor-β (TGF-β), activates Notch signaling in naive CD4+ T cells inducing the production of IL-17 and Th17-related cytokines, IL-22 and IL-23, and the consequent differentiation in Th17 cells. Dll4-mediated Notch activation in naive CD4+ T cells results in the direct transactivation of IL-17 promoter by activating the RBP-Jk/CSL transcription factor (163–165). 2. In addition, ICN may also stimulate Th17 cell differentiation by transactivating the promoter of Ror-γt, a transcription factor required for Th17 differentiation and a main regulator of IL-17. 3. Jagged1-conditioned DCs produce IL-2 that is required for the production of IL-17 by CD25+ cells (166). (B) Notch signaling in γδ T-17 cells. 1. Dll4, upregulated on thymic epithelial cells following IL-6 induction, activates Notch signaling in γδ T-17 cells resulting in expression of HES1, that in turn induces the production of IL-17 and the development of γδ T-17 cells (28, 167). 2. High level of Dll4 in peripheral tissues, such as the intestine and lung, is enable to activate Notch in γδ T-17 cells (28). This results in the production of IL-17, IFN-γ, and tumor necrosis factor α (TNFα) along with the proliferation and activation of peripheral γδ T-17 cells and enhancement of their antitumor cytolytic effect (29).