Abstract
Distal cis-regulatory elements play essential roles in the T lineage-specific expression of cytokine genes. We have mapped interactions of three trans-acting factors-NF-kappaB, STAT4, and T-bet-with cis elements in the Ifng locus. We find that RelA is critical for optimal Ifng expression and is differentially recruited to multiple elements contingent upon T cell receptor (TCR) or interleukin-12 (IL-12) plus IL-18 signaling. RelA recruitment to at least four elements is dependent on T-bet-dependent remodeling of the Ifng locus and corecruitment of STAT4. STAT4 and NF-kappaB therefore cooperate at multiple cis elements to enable NF-kappaB-dependent enhancement of Ifng expression. RelA recruitment to distal elements was similar in T helper 1 (Th1) and effector CD8(+) T (Tc1) cells, although T-bet was dispensable in CD8 effectors. These results support a model of Ifng regulation in which distal cis-regulatory elements differentially recruit key transcription factors in a modular fashion to initiate gene transcription induced by distinct activation signals.
Copyright 2010 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism*
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CD8-Positive T-Lymphocytes / pathology
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Cell Differentiation
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Cells, Cultured
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Chromatin Assembly and Disassembly / genetics
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Interferon-gamma / genetics
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Interferon-gamma / metabolism
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Interleukin-12 / immunology
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Interleukin-12 / metabolism
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Interleukin-18 / immunology
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Interleukin-18 / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / metabolism
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Regulatory Elements, Transcriptional / genetics
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STAT4 Transcription Factor / genetics
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STAT4 Transcription Factor / metabolism*
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / immunology
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T-Box Domain Proteins / metabolism*
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T-bet Transcription Factor
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Th1 Cells / immunology
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Th1 Cells / metabolism*
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Th1 Cells / pathology
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Transcription Factor RelA / genetics
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Transcription Factor RelA / immunology
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Transcription Factor RelA / metabolism*
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Transcriptional Activation
Substances
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Interleukin-18
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NF-kappa B
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Receptors, Antigen, T-Cell
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STAT4 Transcription Factor
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T-Box Domain Proteins
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T-bet Transcription Factor
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Transcription Factor RelA
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Interleukin-12
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Interferon-gamma