Transcription of RORγt in developing Th17 cells is regulated by E-proteins.
In the present study we investigated the molecular mechanisms regulating the expression of RAR-related orphan receptor gamma t (RORγt), 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 RORγt/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 RORγt/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 from studies showing that Id3 deficiency leads to increased IL-4-induced GATA-3 expression, the latter a negative regulator of RORγt transcription; thus, increased Id3 expression likely has a net positive effect on RORγt 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-β, and IL-6, implying that these transcription factors are critical regulators of Th17 induction.
Mucosal Immunity Section, Laboratory of Host Defenses, NIAID, NIH, Bethesda, Maryland, USA.
F
F
Zhang
Mucosal Immunity Section, Laboratory of Host Defenses, NIAID, NIH, Bethesda, Maryland, USA.
I J
IJ
Fuss
Mucosal Immunity Section, Laboratory of Host Defenses, NIAID, NIH, Bethesda, Maryland, USA.
Z
Z
Yang
Mucosal Immunity Section, Laboratory of Host Defenses, NIAID, NIH, Bethesda, Maryland, USA.
W
W
Strober
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D015870:Gene Expression; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D051798:Inhibitor of Differentiation Protein 1; D020381:Interleukin-17; D015850:Interleukin-6; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D016212:Transforming Growth Factor beta; C489532:Tcf12 protein, mouse; C075668:Tcf3 protein, mouse