Abstract
T follicular helper (Tfh) cell is a unique T cell subset specialized in promoting humoral immunity. B-cell lymphoma 6 protein (Bcl6) has been identified as an obligatory transcription factor in Tfh cells; however, the molecular mechanism underlying Bcl6 function remains largely unknown. Here, we defined Bcl6 target genes in Tfh cells by analyzing genome-wide Bcl6 occupancy together with transcriptome profiling. With consensus sequences being different from those in Th9, B cells, and macrophages, Bcl6 binding in Tfh cell was closely associated with a decrease in 5-hydroxymethylcytosine (5hmC). Importantly, Bcl6 promoted Tfh cell differentiation through antagonizing IL-7R (CD127)/signal transducer and activator of transcription (STAT) 5 axis; deletion of the Bcl6 gene in T cells resulted in enhanced IL-7R-STAT5 signaling and substantial expansion of CD127(hi) non-Tfh cells. Thus, our study systemically examines Bcl6-controlled regulatory networks and provides important insights into Bcl6's biological functions in Tfh cells.
Copyright © 2016 The Authors. Published by 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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5-Methylcytosine / analogs & derivatives
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Animals
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B-Lymphocytes / cytology
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B-Lymphocytes / immunology
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Base Sequence
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Cell Differentiation
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Cytosine / analogs & derivatives
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Cytosine / immunology
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / immunology
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Gene Expression Profiling
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Gene Expression Regulation
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Gene Regulatory Networks / immunology*
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Genome-Wide Association Study
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Germinal Center / cytology
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Germinal Center / immunology
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Interleukin-4 / genetics
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Interleukin-4 / immunology
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Interleukins / genetics
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Interleukins / immunology
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Macrophages / cytology
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Macrophages / immunology
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Mice
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Mice, Transgenic
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Molecular Sequence Data
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Proto-Oncogene Proteins c-bcl-6
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Receptors, Interleukin-7 / genetics*
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Receptors, Interleukin-7 / immunology
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STAT5 Transcription Factor / genetics*
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STAT5 Transcription Factor / immunology
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Signal Transduction
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T-Lymphocytes, Helper-Inducer / cytology
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T-Lymphocytes, Helper-Inducer / immunology*
Substances
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Bcl6 protein, mouse
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DNA-Binding Proteins
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Interleukins
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Proto-Oncogene Proteins c-bcl-6
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Receptors, Interleukin-7
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STAT5 Transcription Factor
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Stat5a protein, mouse
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5-hydroxymethylcytosine
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Interleukin-4
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5-Methylcytosine
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Cytosine
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interleukin-21