Abstract
The Src family kinase Lck has been shown to be crucial in T cell signaling and development. However, its role in Th effector functions is not well understood. Lck has previously been shown to play a role in the cytokine expression of Th2 cells, but the mechanism by which Lck influences Th2 effector functions is unknown. Using a mouse model, we report that Lck is important in regulating the expression of IL-4 in Th2 skewed cells but is not as necessary for the expression of Th2 cytokines IL-5, IL-10, and IL-13. Furthermore, in the absence of Lck, T-bet and GATA-3 expression is aberrant. Moreover, this atypical expression pattern of T-bet and GATA-3 correlates with increased histone 3 acetylation at the Ifng locus and production of the Th1 cytokine IFN-gamma. We find overexpression of GATA-3 restores IL-4 expression in lck(-/-) Th2 cells; this indicates that the decreased IL-4 expression is due in part to reduced amounts of GATA-3. Taken together, these data imply that Lck mediates Th2 differentiation through effects on T-bet and GATA-3.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Amino Acid Sequence
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Animals
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Cell Differentiation / genetics
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Cell Differentiation / immunology*
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Cells, Cultured
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GATA3 Transcription Factor / antagonists & inhibitors*
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GATA3 Transcription Factor / biosynthesis
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GATA3 Transcription Factor / genetics
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Gene Expression Regulation / immunology*
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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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Interleukin-4 / antagonists & inhibitors
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Interleukin-4 / biosynthesis
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Interleukin-4 / genetics
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / deficiency
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / physiology*
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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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Molecular Sequence Data
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T-Box Domain Proteins / antagonists & inhibitors*
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T-Box Domain Proteins / biosynthesis
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T-Box Domain Proteins / genetics
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T-bet Transcription Factor
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Th2 Cells / enzymology*
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Th2 Cells / immunology*
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Th2 Cells / metabolism
Substances
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GATA3 Transcription Factor
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GATA3 protein, human
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T-Box Domain Proteins
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T-bet Transcription Factor
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Interleukin-4
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Interferon-gamma
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)