title: The lineage-defining factors T-bet and Bcl-6 collaborate to regulate Th1 gene expression patterns.
abstract: The T-box transcription factor T-bet is important for the differentiation of naive CD4(+) T helper cells (Th cells) into the Th1 phenotype. Much is known about T-bet's role as a transcriptional activator, but less is known about the mechanisms by which T-bet functionally represses alternative Th cell genetic programs. In this study, we first identify Socs1, Socs3, and Tcf7 (TCF-1) as gene targets that are negatively regulated by T-bet. Significantly, T-bet's role in the repression of these genes is through a direct interaction with their promoters. Consistent with this, we identified two T-bet DNA-binding elements in the Socs1 promoter that are functionally used to down-regulate transcription in primary Th1 cells. Importantly, T-bet's novel role in transcriptional repression is because of its ability to physically associate with, and functionally recruit, the transcriptional repressor Bcl-6 to a subset of promoters. Furthermore, T-bet functionally recruits Bcl-6 to the Ifng locus in late stages of Th1 differentiation to repress its activity, possibly to prevent the overproduction of IFN-γ, which could result in autoimmunity. Collectively, these data establish a novel mechanism for T-bet-mediated gene repression in which two lineage-defining transcription factors, one a classical activator and one a repressor, collaborate to promote and properly regulate Th1 development.
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Oestreich
authors.forename: Albert C
authors.initials: AC
authors.lastname: Huang
authors.forename: Amy S
authors.initials: AS
authors.lastname: Weinmann
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D056426:Genetic Loci / Q000235:genetics / Q000276:immunology; D051538:Hepatocyte Nuclear Factor 1-alpha; D051379:Mice; D018345:Mice, Knockout; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020218:Response Elements / Q000235:genetics / Q000276:immunology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051822:T Cell Transcription Factor 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology; D000098815:T-bet Transcription Factor
chemical_list: D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; C491411:Socs3 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051822:T Cell Transcription Factor 1; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor