Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6.
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.
Ozaki
Katsutoshi
K
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
Spolski
Rosanne
R
Ettinger
Rachel
R
Kim
Hyoung-Pyo
HP
Wang
Gang
G
Qi
Chen-Feng
CF
Hwu
Patrick
P
Shaffer
Daniel J
DJ
Akilesh
Shreeram
S
Roopenian
Derry C
DC
Morse
Herbert C
HC
Lipsky
Peter E
PE
Leonard
Warren J
WJ
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002469:Cell Separation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D018655:Lymphocyte Count; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D051757:PAX5 Transcription Factor; D010950:Plasma Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011509:Proteoglycans / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins / Q000096:biosynthesis*; D013154:Spleen / Q000033:anatomy & histology / Q000166:cytology / Q000276:immunology; D053667:Syndecans; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015854:Up-Regulation / Q000276:immunology; D000098546:Interleukin-21
D004268:DNA-Binding Proteins; D007378:Interleukins; D008562:Membrane Glycoproteins; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; C497282:Pax5 protein, mouse; C513258:Prdm1 protein, mouse; D011509:Proteoglycans; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins; D053667:Syndecans; D014157:Transcription Factors; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1; D000098546:Interleukin-21