Abstract
IL-21 is a type I cytokine whose receptor is expressed on T, B, and NK cells. Within the B cell lineage, IL-21 regulates IgG1 production and cooperates with IL-4 for the production of multiple Ab classes in vivo. Using IL-21-transgenic mice and hydrodynamics-based gene delivery of IL-21 plasmid DNA into wild-type mice as well as in vitro studies, we demonstrate that although IL-21 induces death of resting B cells, it promotes differentiation of B cells into postswitch and plasma cells. Thus, IL-21 differentially influences B cell fate depending on the signaling context, explaining how IL-21 can be proapoptotic for B cells in vitro yet critical for Ag-specific Ig production in vivo. Moreover, we demonstrate that IL-21 unexpectedly induces expression of both Blimp-1 and Bcl-6, indicating mechanisms as to how IL-21 can serve as a complex regulator of B cell maturation and terminal differentiation. Finally, BXSB-Yaa mice, which develop a systemic lupus erythematosus-like disease, have greatly elevated IL-21, suggesting a role for IL-21 in the development of autoimmune disease.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / genetics
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Apoptosis / immunology
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B-Lymphocyte Subsets / cytology*
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B-Lymphocyte Subsets / immunology*
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B-Lymphocyte Subsets / metabolism
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Cell Division / genetics
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Cell Division / immunology
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Cell Separation
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Cells, Cultured
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / biosynthesis*
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Humans
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Immunoglobulin Class Switching / genetics
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Interleukins / biosynthesis
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Interleukins / genetics
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Interleukins / physiology*
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Lupus Erythematosus, Systemic / genetics
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Lupus Erythematosus, Systemic / immunology
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Lymphocyte Count
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Membrane Glycoproteins / biosynthesis
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Mutant Strains
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Mice, Transgenic
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PAX5 Transcription Factor
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Plasma Cells / cytology*
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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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Proteoglycans / biosynthesis
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Proto-Oncogene Proteins / biosynthesis*
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Proto-Oncogene Proteins c-bcl-6
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Repressor Proteins / biosynthesis*
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Spleen / anatomy & histology
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Spleen / cytology
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Spleen / immunology
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Syndecans
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / biosynthesis*
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Up-Regulation / immunology
Substances
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DNA-Binding Proteins
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Interleukins
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Membrane Glycoproteins
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PAX5 Transcription Factor
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PAX5 protein, human
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Pax5 protein, mouse
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Prdm1 protein, mouse
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Proteoglycans
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-6
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Repressor Proteins
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Syndecans
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Transcription Factors
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PRDM1 protein, human
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Positive Regulatory Domain I-Binding Factor 1
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interleukin-21