title: Genome-wide regulatory analysis reveals that T-bet controls Th17 lineage differentiation through direct suppression of IRF4.
abstract: The complex relationship between Th1 and Th17 cells is incompletely understood. The transcription factor T-bet is best known as the master regulator of Th1 lineage commitment. However, attention is now focused on the repression of alternate T cell subsets mediated by T-bet, particularly the Th17 lineage. It has recently been suggested that pathogenic Th17 cells express T-bet and are dependent on IL-23. However, T-bet has previously been shown to be a negative regulator of Th17 cells. We have taken an unbiased approach to determine the functional impact of T-bet on Th17 lineage commitment. Genome-wide analysis of functional T-bet binding sites provides an improved understanding of the transcriptional regulation mediated by T-bet, and suggests novel mechanisms by which T-bet regulates Th cell differentiation. Specifically, we show that T-bet negatively regulates Th17 lineage commitment via direct repression of the transcription factor IFN regulatory factor-4 (IRF4). An in vivo analysis of the pathogenicity of T-bet-deficient T cells demonstrated that mucosal Th17 responses were augmented in the absence of T-bet, and we have demonstrated that the roles of T-bet in enforcing Th1 responses and suppressing Th17 responses are separable. The interplay of the two key transcription factors T-bet and IRF4 during the determination of T cell fate choice significantly advances our understanding of the mechanisms underlying the development of pathogenic T cells.
authors.affiliation: Department of Experimental Immunobiology, Division of Transplantation Immunology and Mucosal Biology and Medical Research Council Centre for Transplantation, Guy's Campus, King's College London, London SE1 9RT, United Kingdom;
authors.forename: M Refik
authors.initials: MR
authors.lastname: Gökmen
authors.forename: Rong
authors.initials: R
authors.lastname: Dong
authors.forename: Aditi
authors.initials: A
authors.lastname: Kanhere
authors.forename: Nick
authors.initials: N
authors.lastname: Powell
authors.forename: Esperanza
authors.initials: E
authors.lastname: Perucha
authors.forename: Ian
authors.initials: I
authors.lastname: Jackson
authors.forename: Jane K
authors.initials: JK
authors.lastname: Howard
authors.forename: Maria
authors.initials: M
authors.lastname: Hernandez-Fuentes
authors.forename: Richard G
authors.initials: RG
authors.lastname: Jenner
authors.forename: Graham M
authors.initials: GM
authors.lastname: Lord
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D002478:Cells, Cultured; D002678:Chimera; D003092:Colitis / Q000276:immunology; D004268:DNA-Binding Proteins / Q000172:deficiency; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D017930:Genes, Reporter; D005822:Genetic Vectors; D055106:Genome-Wide Association Study; D050835:Interferon Regulatory Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D038041:Lymphopoiesis / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000502:physiology*; D058504:Th17 Cells / Q000166:cytology*; D014158:Transcription, Genetic; D000098815:T-bet Transcription Factor; D000099218:Interferon Regulatory Factor-4
chemical_list: D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D011993:Recombinant Fusion Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D000099218:Interferon Regulatory Factor-4; C499308:Rag2 protein, mouse