Regulation of B Cell Differentiation and Plasma Cell Generation by IL-21, a Novel Inducer of Blimp-1 and Bcl-6
Open accessAbstract
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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Hypergammaglobulinemia and autoantibody production could be an epiphenomenon of immune activation in autoimmune hepatitis.
“This supports the hypothesis that both hypergammaglobulinemia and autoantibody production could only be an epiphenomenon of the immune activation.”
From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [383]
The discussion section (page unavailable) suggests that elevated IL-21 may account for hypergammaglobulinemia in a mouse model of lupus, linking elevated immunoglobulins to an immune process. It does not address autoimmune hepatitis or establish that hypergammaglobulinemia and autoantibody production are merely epiphenomena of immune activation. (LLM, conf=0.78)
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The IL-4 receptor: signaling mechanisms and biologic functions
Nelms, K., Keegan, A. D., Zamorano, J., Ryan, J. J., & Paul, W. E. (1999) · Annual Review of Immunology · doi:10.1146/annurev.immunol.17.1.701 · Cited by 1,545 · cited 1× · see citing works
“This contrasts to IL-4, which inhibits plasma cell differentiation (29) and induces CD23 expression on mature B cells (30).”
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- Ozaki, K., K. Kikly, D. Michalovich, P. R. Young, and W. J. Leonard. 2000. Cloning of a type I cytokine receptor most related to the IL-2 receptor  chain. Proc. Natl. Acad. Sci. USA 97:11439.
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Crotty, S. (2011) · Annual Review of Immunology · doi:10.1146/annurev-immunol-031210-101400 · Cited by 2,738 · see citing works
Vinuesa, C. G., Cook, M. C., Angelucci, C., Athanasopoulos, V., Rui, L., Hill, K. M., Yu, D., Domaschenz, H., Whittle, B., Lambe, T., et al. (2005) · Nature · doi:10.1038/nature03555 · Cited by 862 · see citing works
Proinflammatory T helper type 17 cells are effective B-cell helpers
Mitsdoerffer, M., Lee, Y., Jäger, A., Kim, H.-J., Korn, T., Kolls, J. K., Cantor, H., Bettelli, E., & Kuchroo, V. K. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1009234107 · Cited by 534 · see citing works
Self-citationLeonard, W. J., & Wan, C.-K. (2016) · F1000Research · doi:10.12688/f1000research.7634.1 · Cited by 184 · see citing works
Self-citationYin–Yang of costimulation: crucial controls of immune tolerance and function
Nurieva, R. I., Liu, X., & Dong, C. (2009) · Immunological Reviews · doi:10.1111/j.1600-065x.2009.00769.x · Cited by 157 · see citing works
The liver as a central "hub" of the immune system: pathophysiological implications
Ronca, V., Gerussi, A., Collins, P., Parente, A., Oo, Y. H., & Invernizzi, P. (2025) · Physiological Reviews · doi:10.1152/physrev.00004.2023 · Cited by 59 · see citing works
Activation of the IL-6/JAK2/STAT3 pathway induces plasma cell mastitis in mice.
Liu, Y., Zhang, J., Zhou, Y.-H., Zhang, H.-M., Wang, K., Ren, Y., Jiang, Y.-N., Han, S.-P., He, J.-J., & Tang, X.-J. (2018) · Cytokine · doi:10.1016/j.cyto.2018.05.002 · Cited by 46 · see citing works
Mittal, D., Caramia, F., Michiels, S., Joensuu, H., Kellokumpu-Lehtinen, P.-L., Sotiriou, C., Loi, S., & Smyth, M. J. (2016) · Cancer Research · doi:10.1158/0008-5472.can-15-1567 · Cited by 27 · see citing works
- Authors
- Ozaki, K., Spolski, R., Ettinger, R., Kim, H.-P., Wang, G., Qi, C.-F., Hwu, P., Shaffer, D. J., Akilesh, S., Roopenian, D. C., Morse, H. C., Lipsky, P. E., & Leonard, W. J.
- Affiliations
- National Heart, Lung, and Blood Institute (US)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (US)
- National Cancer Institute (MY)
- National Institutes of Health (US)
- Jackson Laboratory (US)
- Corresponding author
- Ozaki, Katsutoshi
- Spolski, Rosanne
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-11-01
- Volume
- 173
- Issue
- 9
- Pages
- 5361-5371
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2102364213
- Cited by
- 668
- References
- 1
- Citations by year
- 2026: 11 · 2025: 16 · 2024: 18 · 2023: 18 · 2022: 14 · 2021: 24 · 2020: 18 · 2019: 28 · 2018: 24 · 2017: 25 · 2016: 46 · 2015: 42 · 2014: 47 · 2013: 41 · 2012: 41
- FWCI
- 10.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-56597, R01DK056597)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- IL-21, B cell differentiation, Blimp-1, BCL6, B cell fate, antibody class switching, B cell apoptosis, IL-4, systemic lupus erythematosus, autoimmune disease, type I cytokines
- MeSH terms
- Positive Regulatory Domain I-Binding Factor 1, Interleukin-21, Animals, Cell Division, Cell Separation, Cells, Cultured, DNA-Binding Proteins, Humans, Interleukins, Lupus Erythematosus, Systemic, Membrane Glycoproteins, Mice, Inbred C57BL, Mice, Mutant Strains, Mice, Transgenic, Plasma Cells, Proteoglycans, Proto-Oncogene Proteins, Repressor Proteins, Spleen, Transcription Factors, Up-Regulation, B-Lymphocyte Subsets, Apoptosis, Immunoglobulin Class Switching, Mice, Knockout, Lymphocyte Count, Mice, Proto-Oncogene Proteins c-bcl-6, PAX5 Transcription Factor, Syndecans
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