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* Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute;
Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases;
Surgery Branch, National Cancer Institute,
Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and
¶ The Jackson Laboratory, Bar Harbor, ME 04609
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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D. R. Withers, C. Fiorini, R. T. Fischer, R. Ettinger, P. E. Lipsky, and A. C. Grammer T cell dependent survival of CD20+ and CD20 plasma cells in human secondary lymphoid tissue Blood, June 1, 2007; 109(11): 4856 - 4864. [Abstract] [Full Text] [PDF]
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R. Zeng, R. Spolski, E. Casas, W. Zhu, D. E. Levy, and W. J. Leonard The molecular basis of IL-21-mediated proliferation Blood, May 15, 2007; 109(10): 4135 - 4142. [Abstract] [Full Text] [PDF]
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T. C. Kuo, A. L. Shaffer, J. Haddad Jr., Y. S. Choi, L. M. Staudt, and K. Calame Repression of BCL-6 is required for the formation of human memory B cells in vitro J. Exp. Med., April 16, 2007; 204(4): 819 - 830. [Abstract] [Full Text] [PDF]
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D. Vermijlen, P. Ellis, C. Langford, A. Klein, R. Engel, K. Willimann, H. Jomaa, A. C. Hayday, and M. Eberl Distinct Cytokine-Driven Responses of Activated Blood {gamma}{delta} T Cells: Insights into Unconventional T Cell Pleiotropy J. Immunol., April 1, 2007; 178(7): 4304 - 4314. [Abstract] [Full Text] [PDF]
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D. Herber, T. P. Brown, S. Liang, D. A. Young, M. Collins, and K. Dunussi-Joannopoulos IL-21 Has a Pathogenic Role in a Lupus-Prone Mouse Model and Its Blockade with IL-21R.Fc Reduces Disease Progression J. Immunol., March 15, 2007; 178(6): 3822 - 3830. [Abstract] [Full Text] [PDF]
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R. Ettinger, G. P. Sims, R. Robbins, D. Withers, R. T. Fischer, A. C. Grammer, S. Kuchen, and P. E. Lipsky IL-21 and BAFF/BLyS Synergize in Stimulating Plasma Cell Differentiation from a Unique Population of Human Splenic Memory B Cells J. Immunol., March 1, 2007; 178(5): 2872 - 2882. [Abstract] [Full Text] [PDF]
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A. Frohlich, B. J. Marsland, I. Sonderegger, M. Kurrer, M. R. Hodge, N. L. Harris, and M. Kopf IL-21 receptor signaling is integral to the development of Th2 effector responses in vivo Blood, March 1, 2007; 109(5): 2023 - 2031. [Abstract] [Full Text] [PDF]
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J. Huggins, T. Pellegrin, R. E. Felgar, C. Wei, M. Brown, B. Zheng, E. C. B. Milner, S. H. Bernstein, I. Sanz, and M. S. Zand CpG DNA activation and plasma-cell differentiation of CD27- naive human B cells Blood, February 15, 2007; 109(4): 1611 - 1619. [Abstract] [Full Text] [PDF]
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D. Konforte and C. J. Paige Identification of Cellular Intermediates and Molecular Pathways Induced by IL-21 in Human B Cells J. Immunol., December 15, 2006; 177(12): 8381 - 8392. [Abstract] [Full Text] [PDF]
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H. Jin and T. R. Malek Redundant and unique regulation of activated mouse B lymphocytes by IL-4 and IL-21 J. Leukoc. Biol., December 1, 2006; 80(6): 1416 - 1423. [Abstract] [Full Text] [PDF]
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K. L. Good, V. L. Bryant, and S. G. Tangye Kinetics of Human B Cell Behavior and Amplification of Proliferative Responses following Stimulation with IL-21 J. Immunol., October 15, 2006; 177(8): 5236 - 5247. [Abstract] [Full Text] [PDF]
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L. Rui, J. I. Healy, J. Blasioli, and C. C. Goodnow ERK Signaling Is a Molecular Switch Integrating Opposing Inputs from B Cell Receptor and T Cell Cytokines to Control TLR4-Driven Plasma Cell Differentiation J. Immunol., October 15, 2006; 177(8): 5337 - 5346. [Abstract] [Full Text] [PDF]
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L. Bossaller, J. Burger, R. Draeger, B. Grimbacher, R. Knoth, A. Plebani, A. Durandy, U. Baumann, M. Schlesier, A. A. Welcher, et al. ICOS Deficiency Is Associated with a Severe Reduction of CXCR5+CD4 Germinal Center Th Cells J. Immunol., October 1, 2006; 177(7): 4927 - 4932. [Abstract] [Full Text] [PDF]
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 K.-I Lin, Y.-Y. Kao, H.-K. Kuo, W.-B. Yang, A. Chou, H.-H. Lin, A. L. Yu, and C.-H. Wong Reishi Polysaccharides Induce Immunoglobulin Production through the TLR4/TLR2-mediated Induction of Transcription Factor Blimp-1 J. Biol. Chem., August 25, 2006; 281(34): 24111 - 24123. [Abstract] [Full Text] [PDF]
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E. Arguni, M. Arima, N. Tsuruoka, A. Sakamoto, M. Hatano, and T. Tokuhisa JunD/AP-1 and STAT3 are the major enhancer molecules for high Bcl6 expression in germinal center B cells Int. Immunol., July 1, 2006; 18(7): 1079 - 1089. [Abstract] [Full Text] [PDF]
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D. de Totero, R. Meazza, S. Zupo, G. Cutrona, S. Matis, M. Colombo, E. Balleari, I. Pierri, M. Fabbi, M. Capaia, et al. Interleukin-21 receptor (IL-21R) is up-regulated by CD40 triggering and mediates proapoptotic signals in chronic lymphocytic leukemia B cells Blood, May 1, 2006; 107(9): 3708 - 3715. [Abstract] [Full Text] [PDF]
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B. R. Herrin and L. B. Justement Expression of the Adaptor Protein Hematopoietic Src Homology 2 is Up-Regulated in Response to Stimuli That Promote Survival and Differentiation of B Cells J. Immunol., April 1, 2006; 176(7): 4163 - 4172. [Abstract] [Full Text] [PDF]
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A. Comes, O. Rosso, A. M. Orengo, E. Di Carlo, C. Sorrentino, R. Meazza, T. Piazza, B. Valzasina, P. Nanni, M. P. Colombo, et al. CD25+ Regulatory T Cell Depletion Augments Immunotherapy of Micrometastases by an IL-21-Secreting Cellular Vaccine J. Immunol., February 1, 2006; 176(3): 1750 - 1758. [Abstract] [Full Text] [PDF]
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C. H. Lee, M. Melchers, H. Wang, T. A. Torrey, R. Slota, C.-F. Qi, J. Y. Kim, P. Lugar, H. J. Kong, L. Farrington, et al. Regulation of the germinal center gene program by interferon (IFN) regulatory factor 8/IFN consensus sequence-binding protein J. Exp. Med., January 23, 2006; 203(1): 63 - 72. [Abstract] [Full Text] [PDF]
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R. Ettinger, G. P. Sims, A.-M. Fairhurst, R. Robbins, Y. S. da Silva, R. Spolski, W. J. Leonard, and P. E. Lipsky IL-21 Induces Differentiation of Human Naive and Memory B Cells into Antibody-Secreting Plasma Cells J. Immunol., December 15, 2005; 175(12): 7867 - 7879. [Abstract] [Full Text] [PDF]
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 Z. Wu, H.-P. Kim, H.-H. Xue, H. Liu, K. Zhao, and W. J. Leonard Interleukin-21 Receptor Gene Induction in Human T Cells Is Mediated by T-Cell Receptor-Induced Sp1 Activity Mol. Cell. Biol., November 15, 2005; 25(22): 9741 - 9752. [Abstract] [Full Text] [PDF]
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H.-P. Kim, L. L. Korn, A. M. Gamero, and W. J. Leonard Calcium-dependent Activation of Interleukin-21 Gene Expression in T Cells J. Biol. Chem., July 1, 2005; 280(26): 25291 - 25297. [Abstract] [Full Text] [PDF]
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D. T. Avery, J. I. Ellyard, F. Mackay, L. M. Corcoran, P. D. Hodgkin, and S. G. Tangye Increased Expression of CD27 on Activated Human Memory B Cells Correlates with Their Commitment to the Plasma Cell Lineage J. Immunol., April 1, 2005; 174(7): 4034 - 4042. [Abstract] [Full Text] [PDF]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
