Abstract
The Tec kinases Rlk and Itk are critical for full T cell receptor (TCR)-induced activation of phospholipase C-gamma and mitogen-activated protein kinase. We show here that the mutation of Rlk and Itk impaired activation of the transcription factors NFAT and AP-1 and production of both T helper type 1 (TH1) and TH2 cytokines. Consistent with these biochemical defects, Itk-/- mice did not generate effective TH2 responses when challenged with Schistosoma mansoni eggs. Paradoxically, the more severely impaired Rlk-/-Itk-/- mice were able to mount a TH2 response and produced TH2 cytokines in response to this challenge. In addition, Rlk-/-Itk-/- cells showed impaired TCR-induced repression of the TH2-inducing transcription factor GATA-3, suggesting a potential mechanism for TH2 development in these hyporesponsive cells. Thus, mutations that affect Tec kinases lead to complex alterations in CD4+ TH cell differentiation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Differentiation
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Cells, Cultured
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Cytokines / biosynthesis
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Cytokines / pharmacology
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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GATA3 Transcription Factor
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Immunoglobulin E / biosynthesis
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Lymphocyte Activation
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Mice
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Mice, Knockout
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Mutation
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NFATC Transcription Factors
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Nuclear Proteins*
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Protein-Tyrosine Kinases / genetics*
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Protein-Tyrosine Kinases / physiology*
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RNA, Messenger / biosynthesis
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Receptors, Antigen, T-Cell / physiology
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Schistosomiasis mansoni / immunology
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Schistosomiasis mansoni / pathology
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T-Lymphocytes, Helper-Inducer / drug effects
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T-Lymphocytes, Helper-Inducer / enzymology*
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T-Lymphocytes, Helper-Inducer / immunology*
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Th2 Cells / enzymology
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Th2 Cells / immunology
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Trans-Activators / biosynthesis
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Trans-Activators / genetics
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Transcription Factor AP-1 / metabolism
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Transcription Factors / metabolism
Substances
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Cytokines
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DNA-Binding Proteins
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GATA3 Transcription Factor
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Gata3 protein, mouse
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NFATC Transcription Factors
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Nuclear Proteins
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RNA, Messenger
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Receptors, Antigen, T-Cell
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Trans-Activators
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Transcription Factor AP-1
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Transcription Factors
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Immunoglobulin E
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Tec protein-tyrosine kinase
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Protein-Tyrosine Kinases
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emt protein-tyrosine kinase