Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6.

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B-Lymphocyte-Subsets, Cell-Division, Cell-Separation, Cells-Cultured, DNA-Binding-Proteins, Humans, Immunoglobulin-Class-Switching, Interleukins, Lupus-Erythematosus-Systemic, Lymphocyte-Count, Membrane-Glycoproteins, Mice-Inbred-C57BL, Mice-Knockout, Mice-Mutant-Strains, Mice-Transgenic, Plasma-Cells, Proteoglycans, Proto-Oncogene-Proteins, Repressor-Proteins, Spleen, Transcription-Factors, Up-Regulation

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J Immunol 2004 Nov; 173(9):5361-71.


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.

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