Abstract
In response to antigens and cytokines, mouse B cells undergo class-switch recombination (CSR) and differentiate into Ig-secreting cells. T-bet, a T-box transcription factor that is up-regulated in lymphocytes by IFN-γ or IL-27, was shown to regulate CSR to IgG2a after T cell-independent B-cell stimulations. However, the molecular mechanisms controlling this process remain unclear. In the present study, we show that inactivation of the Ets-1 transcription factor results in a severe decrease in IgG2a secretion in vivo and in vitro. No T-bet expression was observed in Ets-1-deficient (Ets-1(-/-)) B cells stimulated with IFN-γ and lipopolysaccharide, and forced expression of T-bet in these cells rescued IgG2a secretion. Furthermore, we identified a transcriptional enhancer in the T-bet locus with an activity in B cells that relies on ETS-binding sites. After IFN-γ stimulation of Ets-1(-/-) B cells, activated Stat1, which forms a complex with Ets-1 in wild-type cells, no longer binds to the T-bet enhancer or promotes histone modifications at this site. These results demonstrate that Ets-1 is critical for IgG2a CSR and acts as an essential cofactor for Stat1 in the regulation of T-bet expression in B cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Animals
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B-Lymphocytes / immunology
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B-Lymphocytes / metabolism*
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DNA-Binding Proteins / deficiency
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Enhancer Elements, Genetic
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Gene Expression Regulation
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Histones / metabolism
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Immunoglobulin Class Switching / genetics
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Immunoglobulin Class Switching / physiology*
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Immunoglobulin G / biosynthesis*
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Interferon-gamma / pharmacology
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Interleukin Receptor Common gamma Subunit / deficiency
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Lipopolysaccharides / pharmacology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Protein Processing, Post-Translational
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Proto-Oncogene Protein c-ets-1 / deficiency
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Proto-Oncogene Protein c-ets-1 / genetics
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Proto-Oncogene Protein c-ets-1 / physiology*
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STAT1 Transcription Factor / deficiency
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STAT1 Transcription Factor / genetics
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STAT1 Transcription Factor / physiology*
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Specific Pathogen-Free Organisms
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T-Box Domain Proteins / biosynthesis
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / physiology*
Substances
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DNA-Binding Proteins
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Ets1 protein, mouse
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Histones
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Immunoglobulin G
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Interleukin Receptor Common gamma Subunit
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Lipopolysaccharides
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Proto-Oncogene Protein c-ets-1
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Rag2 protein, mouse
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STAT1 Transcription Factor
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Stat1 protein, mouse
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T-Box Domain Proteins
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T-box transcription factor TBX21
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Interferon-gamma