Abstract
The transcription factor IRF4 regulates immunoglobulin class switch recombination and plasma cell differentiation. Its differing concentrations appear to regulate mutually antagonistic programs of B and plasma cell gene expression. We show IRF4 to be also required for generation of germinal center (GC) B cells. Its transient expression in vivo induced the expression of key GC genes including Bcl6 and Aicda. In contrast, sustained and higher concentrations of IRF4 promoted the generation of plasma cells while antagonizing the GC fate. IRF4 cobound with the transcription factors PU.1 or BATF to Ets or AP-1 composite motifs, associated with genes involved in B cell activation and the GC response. At higher concentrations, IRF4 binding shifted to interferon sequence response motifs; these enriched for genes involved in plasma cell differentiation. Our results support a model of "kinetic control" in which signaling-induced dynamics of IRF4 in activated B cells control their cell-fate outcomes.
Copyright © 2013 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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B-Lymphocytes / immunology*
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Basic-Leucine Zipper Transcription Factors / metabolism
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Cell Differentiation
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Cytidine Deaminase / genetics
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Gene Expression Regulation
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Germinal Center / immunology
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Germinal Center / metabolism*
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Interferon Regulatory Factors / genetics
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Interferon Regulatory Factors / metabolism*
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology
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Mice
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Mice, Transgenic
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Plasma Cells / immunology
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Plasma Cells / metabolism*
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Positive Regulatory Domain I-Binding Factor 1
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Proto-Oncogene Protein c-ets-1 / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-6
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Trans-Activators / metabolism
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Transcription Factor AP-1 / immunology
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Transcription Factor AP-1 / metabolism
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Transcription Factors / metabolism
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Transcription, Genetic
Substances
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Basic-Leucine Zipper Transcription Factors
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Batf protein, mouse
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Bcl6 protein, mouse
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DNA-Binding Proteins
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Interferon Regulatory Factors
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Pou2af1 protein, mouse
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Prdm1 protein, mouse
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Proto-Oncogene Protein c-ets-1
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-6
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Trans-Activators
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Transcription Factor AP-1
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Transcription Factors
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interferon regulatory factor-4
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proto-oncogene protein Spi-1
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Positive Regulatory Domain I-Binding Factor 1
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AICDA (activation-induced cytidine deaminase)
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Cytidine Deaminase