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* Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892; and
Ultramicro Analytical Immunochemistry Resource Division of Bioengineering and Physical Science, Office of Research Services, National Institutes of Health, Bethesda, MD 20892
During T cell-B cell collaboration, plasma cell (PC) differentiation and Ig production are known to require T cell-derived soluble factors. However, the exact nature of the cytokines produced by activated T cells that costimulate PC differentiation is not clear. Previously, we reported that costimulation of purified human B cells with IL-21 and anti-CD40 resulted in efficient PC differentiation. In this study, we addressed whether de novo production of IL-21 was involved in direct T cell-induced B cell activation, proliferation, and PC differentiation. We found that activated human peripheral blood CD4+ T cells expressed mRNA for a number of cytokines, including IL-21, which was confirmed at the protein level. Using a panel of reagents that specifically neutralize cytokine activity, we addressed which cytokines are essential for B cell activation and PC differentiation induced by anti-CD3-activated T cells. Strikingly, neutralization of IL-21 with an IL-21R fusion protein (IL-21R-Fc) significantly inhibited T cell-induced B cell activation, proliferation, PC differentiation, and Ig production. Inhibition of PC differentiation was observed even when the addition of IL-21R-Fc was delayed until after initial B cell activation and expansion had occurred. Importantly, IL-21 was found to be involved in PC differentiation from both naive and memory B cells. Finally, IL-21R-Fc did not inhibit anti-CD3-induced CD4+ T cell activation, but rather directly blocked T cell-induced B cell activation and PC differentiation. These data are the first to document that B cell activation, expansion, and PC differentiation induced by direct interaction of B cells with activated T cells requires IL-21.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported (in part) by the intramural program of National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. S.K. was supported by the Jean et Linette Warnery Foundation and the Swiss Foundation for Medical-Biological Scholarships.
2 Current address: Inflammation and Autoimmunity, MedImmune, One MedImmune Way, 25A32, Gaithersburg, MD 20878.
3 Address correspondence and reprint requests to Dr. Rachel Ettinger, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Building 10, Room 6D-47B, Bethesda, MD 20892. E-mail address: ettingerr{at}mail.nih.gov
4 Abbreviations used in this paper: PC, plasma cell; BAFF/BLyS, B cell-activating factor belonging to the TNF family; ion, ionomycin; PI, propidium iodide; FSC, forward scatter; 
2M, 2 microglobulin; ICE, immunoaffinity capillary electrophoresis.
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