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Address correspondence to Rafi Ahmed, rahmed@emory.edu.

Present address: Donald R. Latner and Rachael D. Aubert, Centers for Disease Control and Prevention, Atlanta, Georgia, USA; William A. Langley, Medical Neurogenetics LLC, Atlanta, Georgia, USA; Sang-Jun Ha, Department of Biochemistry, College of Life Science and Engineering, Yonsei Univeristy, Seoul, South Korea; Surojit Sarkar and Vandana Kalia, Department of Veterinary and Biomedical Sciences, College of Agricultural Sciences, Penn State University, University Park, Pennsylvania, USA.

We thank the NIH tetramer core facility (Emory University, Atlanta, GA) for providing MHC class II tetramer IAb-gp66-77 for LCMV.

We thank Rama S. Akondy for careful reading of the manuscript.

W.J.L. and R.S. are inventors on patents and patent applications related to IL-21.

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Research Funding:

This work was supported by National Institutes of Health (NIH) grants P01 AI097092-01A1; (to R.A.) and RO1 A1030048 (to R.A.) and Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery grant UM1AI100663 (to R.A.).

This work was also supported in part by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH (to W.J.L. and R.S.).

Interleukin-21 Is a Critical Cytokine for the Generation of Virus-Specific Long-Lived Plasma Cells

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Journal Title:

Journal of Virology

Volume:

Volume 87, Number 13

Publisher:

, Pages 7737-7746

Type of Work:

Article | Final Publisher PDF

Abstract:

Long-lived plasma cells that reside in the bone marrow constitutively produce antibody in the absence of antigen and are the cellular basis of durable humoral immunity. The generation of these long-lived plasma cells depends upon a series of highly orchestrated interactions between antigen-specific CD4 T cells and B cells and the formation of germinal centers (GCs). In this study, we have examined the role of the cytokine interleukin-21 (IL-21) in regulating humoral immunity during acute viral infections. Using IL-21 receptor-deficient (IL-21R−/−) mice, we found that virus-specific CD4 T cells were generated after infection with lymphocytic choriomeningitis virus (LCMV) and that these CD4 T cells differentiated into T follicular helper (TFH)-like cells in the absence of IL-21 signaling. There was also no defect in the formation of GCs, although after day 15 these GCs disappeared faster in IL-21R−/− mice than in wild-type mice. Isotype switching and the initial LCMV-specific IgG response were normal in IL-21R−/− mice. However, these mice exhibited a profound defect in generating long-lived plasma cells and in sustaining antibody levels over time. Similar results were seen after infection of IL-21R−/− mice with vesicular stomatitis virus and influenza virus. Using chimeric mice containing wild-type or IL-21R−/− CD4 T cells and B cells, we showed that both B and CD4 T cells need IL-21 signaling for generating long-term humoral immunity. Taken together, our results highlight the importance of IL-21 in humoral immunity to viruses.

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© 2013, American Society for Microbiology. All Rights Reserved.

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