Transcriptional factor E2A regulates the differentiation of Th17 cells (69.10)

Abstract

Abstract The molecular mechanisms that direct transcription of the gene encoding the transcription factor RORγt, a master regulator of Th17 cells, remain ill-defined. We previously showed that transcription factor E2A is enriched at the Foxp3 promoter and regulates the differentiation of regulatory T cells in response to TGF-β. Since TGF-β is also required to generate Th17 cells, we hypothesized that E2A might also be involved in the differentiation of Th17 cells. We utilized Id3 deficient mice, as Id3 is reported to inhibit E2A binding to DNA, and found that Id3 deficient mice had a much greater frequency and absolute number of Th17 cells in the lamina propria and Peyer’s patches. In vitro study showed that Id3 deficient CD4(+)CD25(-) naïve T cells showed greater differentiation into Th17 cells in response to TGF-β1 plus IL-6. Treatment with TGF-β1 substantially enriched E2A at the Rorc promoter in naïve CD4(+) T cells. In addition, E2A knockdown by siRNA resulted much less Rorc transcription and IL-17 production in CD4(+) T cells stimulated with TGF-β1 plus IL-6. These data suggest that E2A plays an important role in promoting the RORγt expression through enrichment to Rorc promoter and the consequent Th17 differentiation. We plan to investigate how IL-6-mediated signaling pathway is integrated with E2A-mediated Rorc activation in directing IL-17 production in CD4(+) T cells.