Abstract
Upon recognition of antigen, B cells undertake a bifurcated response in which some cells rapidly differentiate into plasmablasts while others undergo affinity maturation in germinal centers (GCs). Here we identified a double-negative feedback loop between the transcription factors IRF4 and IRF8 that regulated the initial developmental bifurcation of activated B cells as well as the GC response. IRF8 dampened signaling via the B cell antigen receptor (BCR), facilitated antigen-specific interaction with helper T cells, and promoted antibody affinity maturation while antagonizing IRF4-driven differentiation of plasmablasts. Genomic analysis revealed concentration-dependent actions of IRF4 and IRF8 in regulating distinct gene-expression programs. Stochastic modeling suggested that the double-negative feedback was sufficient to initiate bifurcation of the B cell developmental trajectories.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Algorithms
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Animals
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B-Lymphocytes / immunology*
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B-Lymphocytes / metabolism
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Blotting, Western
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Cell Differentiation / immunology
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Cells, Cultured
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Feedback, Physiological
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Flow Cytometry
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Germinal Center / cytology
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Germinal Center / immunology
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Interferon Regulatory Factors / deficiency
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Interferon Regulatory Factors / genetics
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Interferon Regulatory Factors / immunology*
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Lymphocyte Activation / immunology*
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Models, Immunological
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Plasma Cells / immunology
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Plasma Cells / metabolism
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Receptors, Antigen, B-Cell / immunology
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / immunology*
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T-Lymphocytes, Helper-Inducer / immunology
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T-Lymphocytes, Helper-Inducer / metabolism
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Transcriptome / genetics
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Transcriptome / immunology
Substances
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Interferon Regulatory Factors
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Receptors, Antigen, B-Cell
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interferon regulatory factor-4
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interferon regulatory factor-8
Associated data
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GEO/GSE70710
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GEO/GSE70711
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GEO/GSE70712