Transcription of RORgt in developing Th17 cells is regulated by E-proteins

Abstract

In the present study we investigated the molecular mechanisms regulating the expression of RAR-related orphan receptor gamma t (RORct), the central factor controlling interleukin (IL)-17 transcription and Th17 differentiation. In key studies, we found that cells from mice with major deletions of E-protein transcription factors, E2A and HEB, display greatly reduced RORct/IL-17 expression and that E-protein-deficient mice exhibit greatly diminished IL-17-dependent inflammation in experimental allergic encephalitis models. In additional studies, we unexpectedly found that cells from mice with deletion of Id3, a protein that inhibits E-protein binding to DNA, display diminished RORct/IL-17 expression and mice deficient in this protein exhibit decreased Th17-mediated inflammation in a cell-transfer colitis model. The explanation of these initially paradoxical findings came fromstudies showing that Id3 deficiency leads to increased IL-4- induced GATA-3 expression, the latter a negative regulator of RORct transcription; thus, increased Id3 expression likely has a net positive effect on RORct expression via its inhibition of IL-4 production. Finally, we found that both E-proteins and Id3 are upregulated in tandem by the cytokines that induce Th17 differentiation, transforming growth factor-b, and IL-6, implying that these transcription factors are critical regulators of Th17 induction. © 2014 Society for Mucosal Immunology.