Abstract
Molecular mechanisms underlying the coordination of isotype switching with plasma cell differentiation are poorly understood. We show that interferon regulatory factor-4 (IRF-4) regulates both processes by controlling the expression of the Aicda and Prdm1 genes, which encode AID and Blimp-1, respectively. Genome-wide analysis demonstrated that Irf4(-/-) B cells failed to induce the entire Blimp-1-dependent plasma cell program. Restoration of AID or Blimp-1 expression in Irf4(-/-) B cells promoted isotype switching or secretion, respectively. IRF-4 was expressed in a graded manner in differentiating B cells and targeted Prdm1. Higher concentration of IRF-4 induced Prdm1 and consequently the transition from a germinal center gene expression program to that of a plasma cell. We propose a gene-regulatory network in which graded expression of IRF-4 developmentally coordinates isotype switching with plasma cell differentiation.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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B-Lymphocytes / cytology
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B-Lymphocytes / immunology
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B-Lymphocytes / metabolism
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Cell Differentiation*
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Cell Proliferation
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Cells, Cultured
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Cytidine Deaminase / metabolism
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DNA / genetics
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DNA-Binding Proteins / metabolism
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Gene Expression Profiling
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Genome / genetics
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Immunoglobulin Class Switching / immunology*
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Immunoglobulin G / immunology
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Immunoglobulin Isotypes / genetics
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Immunoglobulin Isotypes / 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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Interferon Regulatory Factors / metabolism*
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Mice
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Mice, Knockout
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Plasma Cells / cytology*
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Plasma Cells / immunology*
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Positive Regulatory Domain I-Binding Factor 1
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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DNA-Binding Proteins
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Immunoglobulin G
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Immunoglobulin Isotypes
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Interferon Regulatory Factors
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Prdm1 protein, mouse
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Repressor Proteins
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Transcription Factors
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interferon regulatory factor-4
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DNA
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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