Abstract
Ikaros, a hematopoietic transcription factor, has well defined effects on early lymphocyte development in the bone marrow and thymus. In this study we demonstrate that Ikaros is a positive regulator of Th2 cytokine gene expression in peripheral T cells. CD4+ T cells from naive Ikaros(null) mice cultured under Th2-skewing conditions express the Th1 cytokine IFN-gamma and have reduced IL-4, IL-5, and IL-13 expression. Ikaros directly associates with several Th2 locus regulatory regions in naive CD4+ T cells. The decreased ability to express Th2 cytokines in Ikaros(null)T cells corresponds with histone 3 hypoacetylation across the Th2 cytokine locus as well as decreased GATA3 and cMaf and increased T-bet and STAT1 expression. These data support a model whereby Ikaros directly activates Th2 gene expression by promoting local chromatin accessibility during CD4+ T cell differentiation and also acts indirectly to regulate expression of Th2- and Th1-specific transcription factors.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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Cell Differentiation / immunology*
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Cells, Cultured
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Chromatin / genetics
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Chromatin / metabolism
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Gene Expression Regulation / immunology
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Hematopoiesis / genetics
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Hematopoiesis / immunology
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Ikaros Transcription Factor / deficiency
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Ikaros Transcription Factor / genetics
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Ikaros Transcription Factor / metabolism
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Ikaros Transcription Factor / physiology*
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Interferon-gamma / biosynthesis
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Interferon-gamma / genetics
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Interferon-gamma / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Models, Immunological
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Protein Binding / genetics
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Protein Binding / immunology
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Th1 Cells / immunology
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Th1 Cells / metabolism
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Th2 Cells / cytology*
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Th2 Cells / immunology*
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Th2 Cells / metabolism
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Transcriptional Activation / immunology
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Up-Regulation / genetics
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Up-Regulation / immunology*
Substances
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Chromatin
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Zfpn1a1 protein, mouse
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Ikaros Transcription Factor
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Interferon-gamma