Oestreich, Kenneth J.Huang, A. C.Weinmann, A. S.2017-01-092017-01-092011-05-090022-1007http://hdl.handle.net/10919/74033The 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.1001 - 1013 (13) page(s)application/pdfenCreative Commons Attribution-NonCommercial-ShareAlike 3.0 UnportedImmunologyMedicine, Research & ExperimentalResearch & Experimental MedicineTRANSCRIPTION FACTOR GATA-3INTERFERON-GAMMACELL-DIFFERENTIATIONCYTOKINE SIGNALING-1TARGET GENESSUPPRESSORCOMMITMENTSOCS-3FATEPLASTICITYArticle - RefereedThe Author(s)https://doi.org/10.1084/jem.201021442085