Abstract
Certain IFN regulatory factor (IRF) transcription factors indirectly influence T helper (Th) cell differentiation by regulating the production of IL-12. Here, we show that IRF4 directly regulates Th cell differentiation in vitro and in vivo during murine leishmaniasis. In the absence of IRF4, IL-12-induced Th1 cell differentiation was compromised, while IL-4 failed to induce Th2 cell differentiation. Instead, IL-4 tended to induce Th1 cells, defined by production of IFN-gamma and TNF. Although early IL-4 signaling was normal in IRF4(-/-) Th cells, the protein GATA-3, a transcription factor critical for Th2 development, was not up-regulated following IL-4 treatment. Retroviral overexpression of GATA-3 rescued Th2 differentiation. Therefore, IRF4 deficiency manifests itself as severely dysregulated Th cell differentiation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Cell Differentiation / physiology*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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GATA3 Transcription Factor
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Gene Expression Regulation / drug effects
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Interferon Regulatory Factors
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Interleukin-4 / pharmacology
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Leishmaniasis / immunology
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Leishmaniasis / pathology
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Mice
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Mice, Inbred C57BL
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Phosphorylation
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STAT6 Transcription Factor
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T-Lymphocytes, Helper-Inducer / cytology*
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T-Lymphocytes, Helper-Inducer / drug effects
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription Factors / physiology*
Substances
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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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Interferon Regulatory Factors
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STAT6 Transcription Factor
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Stat6 protein, mouse
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Trans-Activators
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Transcription Factors
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interferon regulatory factor-4
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Interleukin-4