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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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Submitted November 15, 2006
Accepted June 12, 2007

Identification of a distant T-bet enhancer responsive to IL-12/Stat4 and IFN{gamma}/Stat1 signals

Yu Yang, Jordi C Ochando, Jonathan S Bromberg, and Yaozhong Ding*

Depts of Gene and Cell Medicine, Surgery, & Center for Immunobiology, Mount Sinai School of Medicine, New York, NY, United States

* Corresponding author; email: yaozhong.ding{at}mssm.edu.

T-bet plays a critical role in controlling IFN{gamma} expression, Th1 polarization, and CD8 cytolytic development. Its regulation has been demonstrated to be mostly IFN{gamma}/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{gamma}/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{gamma} 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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