Notch signaling regulates human and mouse TH17 development. (139.13)

Abstract TH17 immune cells, a recently discovered subset of CD4+ T-helper cells, are known to play important role in pathogenesis of several autoimmune diseases, inflammatory disorders and cancers. Although Notch ligand DLL4 was shown to drive TH17 polarization, downstream pathways conducting those signals are unknown. We demonstrated that the Notch signaling pathway has an important role in TH17 polarization. We found that gamma secretase inhibitors (GSI) that inhibit Notch signaling blocked the in-vitro polarization of mouse or human naïve CD4+ T cells towards the TH17 pathway without affecting cell proliferation. Next, we showed that, among various Notch receptors, Notch-1 is upregulated in TH17 polarizing cells and that knocking down Notch-1 by siRNA inhibited TH17 polarization. We further discovered that, in addition to polarizing naïve T cells towards TH17 pathway, Notch-1 is important for maintenance of this phenotype. Furthermore, reporter luciferase assays and chromatin immunoprecipitation (ChIP) assays suggest that the IL-17 as well as RORC promoters are direct transcriptional targets of Notch-1. Finally, in-vivo administration of GSI inhibits TH17 mediated disease progression in mouse experimental autoimmune encephalomyelitis model of multiple sclerosis. Thus our data suggest a key role for Notch signaling, especially Notch-1, in TH17 polarization.