Abstract
Interleukin-12 (IL-12) is a key cytokine for the development of T helper type 1 (Th1) responses; however, naïve CD4(+) T cells do not express IL-12Rbeta2, and are therefore unresponsive to IL-12. We have examined the mechanisms that control Th1-specific expression of the human IL-12Rbeta2 gene at early time points after T-cell stimulation. We have identified a Th1-specific enhancer element that binds signal transducer and activator of transcription 4 (STAT4) in vivo in developing Th1 but not Th2 cells. T-cell receptor (TCR) signaling induced histone hyperacetylation and recruitment of BRG1, the ATPase subunit of the SWI/SNF-like BAF chromatin remodeling complex, to the IL-12Rbeta2 regulatory regions and was associated with low-level gene transcription at the IL-12Rbeta2 locus. However, high-level IL-12Rbeta2 expression required TCR triggering in the presence of IL-12. Our results indicate a synergistic role of TCR-induced chromatin remodeling and cytokine-induced STAT4 activation to direct IL-12Rbeta2 expression during Th1 cell development.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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Cell Differentiation / drug effects
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Cell Differentiation / genetics*
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Cell Differentiation / immunology
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Chromatin / metabolism*
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Chromatin Immunoprecipitation
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Chromosomal Proteins, Non-Histone / genetics
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Chromosomal Proteins, Non-Histone / metabolism*
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GATA3 Transcription Factor / genetics
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GATA3 Transcription Factor / metabolism
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Gene Expression Regulation / drug effects
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Humans
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Interferon-alpha / pharmacology
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Interferon-gamma / genetics
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Interferon-gamma / pharmacology
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Interleukin-12 / pharmacology
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Interleukin-4 / pharmacology
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Models, Biological
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Promoter Regions, Genetic / genetics
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Protein Binding / drug effects
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RNA Interference
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Receptors, Interleukin-12 / genetics*
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Receptors, Interleukin-12 / immunology
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Receptors, Interleukin-12 / metabolism
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STAT4 Transcription Factor / genetics*
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STAT4 Transcription Factor / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Th1 Cells / cytology
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Th1 Cells / immunology
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Th1 Cells / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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Chromatin
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Chromosomal Proteins, Non-Histone
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GATA3 Transcription Factor
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Interferon-alpha
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Receptors, Interleukin-12
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STAT4 Transcription Factor
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SWI-SNF-B chromatin-remodeling complex
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Transcription Factors
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Interleukin-12
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Interleukin-4
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Interferon-gamma