Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adenoviridae / genetics
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Animals
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Base Sequence
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CD4-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / metabolism
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Cells, Cultured
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Gene Expression Regulation
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Genes, Reporter
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Interferon-gamma / pharmacology*
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Interleukin-12 / metabolism*
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Mice
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Mice, Transgenic
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Molecular Sequence Data
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Protein Binding
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STAT1 Transcription Factor / metabolism*
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STAT4 Transcription Factor / deficiency
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STAT4 Transcription Factor / genetics
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STAT4 Transcription Factor / metabolism*
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Sequence Alignment
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Signal Transduction* / drug effects
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / metabolism*
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T-bet Transcription Factor
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Transcriptional Activation / genetics
Substances
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STAT1 Transcription Factor
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STAT4 Transcription Factor
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Stat1 protein, mouse
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T-Box Domain Proteins
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T-bet Transcription Factor
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Interleukin-12
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Interferon-gamma