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IL-21-Induced Isotype Switching to IgG and IgA by Human Naive B Cells Is Differentially Regulated by IL-4¹

Danielle T. Avery^2,*,, Vanessa L. Bryant^2,3,*,,, Cindy S. Ma^2,*,, Rene de Waal Malefyt and Stuart G. Tangye^4,*,,

^* Immunology and Inflammation Group, Garvan Institute of Medical Research, Sydney, New South Wales, Australia; Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales, Australia; Department of Experimental Medicine, University of Sydney, Sydney New South Wales, Australia; and Schering Plough Biopharma (formerly DNAX), Palo Alto, CA 94304

Naive B cells can alter the effector function of their Ig molecule by isotype switching, thereby allowing them to secrete not only IgM, but also the switched isotypes IgG, IgA, and IgE. Different isotypes are elicited in response to specific pathogens. Similarly, dysregulated production of switched isotypes underlies the development of various diseases, such as autoimmunity and immunodeficiency. Thus, it is important to characterize mediators controlling isotype switching, as well as their contribution to the overall B cell response. Isotype switching in human naive B cells can be induced by CD40L together with IL-4, IL-10, IL-13, and/or TGF-β. Recently, IL-21 was identified as a switch factor for IgG1 and IgG3. However, the effect of IL-21 on switching to IgA, as well as the interplay between IL-21 and other switch factors, remains unknown. We found that IL-4 and IL-21 individually induced CD40L-stimulated human naive B cells to undergo switching to IgG, with IL-4 predominantly inducing IgG1⁺ cells and IL-21 inducing IgG3. Culture of naive B cells with CD40L and IL-21, but not IL-4, also yielded IgA⁺ cells. Combining IL-4 and IL-21 had divergent effects on isotype switching. Specifically, while IL-4 and IL-21 synergistically increased the generation of IgG1⁺ cells from CD40L-stimulated B cells, IL-4 concomitantly abolished IL-21-induced switching to IgA. Our findings demonstrate the dynamic interplay between IL-4 and IL-21 in regulating the production of IgG subclasses and IgA, and suggest temporal roles for these cytokines in humoral immune responses to specific pathogens.

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 by the National Health and Medical Research Council of Australia. V.L.B. was the recipient of a Postgraduate Research Award from the University of Sydney. C.S.M. and S.G.T. are recipients of Research Fellowships awarded by the National Health and Medical Research Council. DNAX is wholly funded by Schering Plough.

² D.T.A., V.L.B., and C.S.M. contributed equally to this work.

³ Current address: Leonard Wagner Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, NY 10021.

⁴ Address correspondence and reprint requests to Dr. Stuart Tangye, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst 2010, New South Wales, Australia. E-mail address: s.tangye{at}garvan.org.au

⁵ Abbreviations used in this paper: DC, dendritic cell; BAFF, B cell-activating factor belonging to the TNF family; APRIL, a proliferation-inducing ligand; GLT, germline transcript; SA, streptavidin; PB, peripheral blood; CB, cord blood; T_FH, T follicular helper.

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