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Blood, 1 October 2007, Vol. 110, No. 7, pp. 2494-2500.
Prepublished online as a Blood First Edition Paper on June 15, 2007; DOI 10.1182/blood-2006-11-058271.
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IMMUNOBIOLOGY
Identification of a distant T-bet enhancer responsive to IL-12/Stat4 and IFN /Stat1 signals
Yu Yang1,
Jordi C. Ochando1,
Jonathan S. Bromberg1,4, and
Yaozhong Ding1,4
Departments of1 Gene and Cell Medicine, and
2 Surgery,
3 Center for Immunobiology, and
4 The Recanati/Miller Transplantation Institute, Mount Sinai School of Medicine, New York, NY
T-bet plays a critical role in controlling IFN expression, Th1 polarization, and CD8 cytolytic development. Its regulation has been demonstrated to be mostly IFN /Stat1 dependent while IL-12/Stat4 independent. Here we show that IL-12/Stat4 binds to a distant highly conserved STAT-responsive T-bet enhancer, and induces IFN /Stat1-independent T-bet expression in CD8 T cells. Luciferase reporter assay showed that both Stat4 and Stat1 activate reporter gene expression from constructs containing a wild-type but not mutated T-bet enhancer. Studies in virus-infected mice demonstrated that the IL-12/Stat4/T-bet cascade operates in vivo and regulates IFN in CD8 T cells. Together, we provide a novel mechanism for T-bet regulation, and suggest that IL-12/Stat4/T-bet play an important role in CD8 effector responses.

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