Identification of a distant T-bet enhancer responsive to IL-12/Stat4 and IFNgamma/Stat1 signals.
T-bet plays a critical role in controlling IFNgamma expression, Th1 polarization, and CD8 cytolytic development. Its regulation has been demonstrated to be mostly IFNgamma/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 IFNgamma/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 IFNgamma 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.
Yang
Yu
Y
Departments of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Ochando
Jordi C
JC
Bromberg
Jonathan S
JS
Ding
Yaozhong
Y
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D007371:Interferon-gamma / Q000494:pharmacology*; D018664:Interleukin-12 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011485:Protein Binding; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050797:STAT4 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction / Q000187:drug effects; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D000098815:T-bet Transcription Factor
D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; C494080:Stat1 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12; D007371:Interferon-gamma