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Cytokine-Mediated Regulation of Human B Cell Differentiation into Ig-Secreting Cells: Predominant Role of IL-21 Produced by CXCR5⁺ T Follicular Helper Cells¹

Vanessa L. Bryant^2,*,,, Cindy S. Ma^*,, Danielle T. Avery^*,, Ying Li, Kim L. Good^3,*,,, Lynn M. Corcoran^¶, Rene de Waal Malefyt and Stuart G. Tangye^4,*,,

^* Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia; Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales, Australia; and Department of Experimental Medicine, University of Sydney, Sydney, New South Wales, Australia; Schering Plough Biopharma (formerly DNAX), Palo Alto, CA 94304; and ^¶ Walter and Eliza Hall Institute, Parkville, Victoria, Australia

Differentiation of B cells into Ig-secreting cells (ISC) is critical for the generation of protective humoral immune responses. Because of the important role played by secreted Ig in host protection against infection, it is necessary to identify molecules that control B cell differentiation. Recently, IL-21 was reported to generate ISC from activated human B cells. In this study, we examined the effects of IL-21 on the differentiation of all human mature B cell subsets—neonatal, transitional, naive, germinal center, IgM-memory, and isotype-switched memory cells—into ISC and compared its efficacy to that of IL-10, a well-known mediator of human B cell differentiation. IL-21 rapidly induced the generation of ISC and the secretion of vast quantities IgM, IgG and IgA from all of these B cell subsets. Its effect exceeded that of IL-10 by up to 100-fold, highlighting the potency of IL-21 as a B cell differentiation factor. Strikingly, IL-4 suppressed the stimulatory effects of IL-21 on naive B cells by reducing the expression of B-lymphocyte induced maturation protein-1 (Blimp-1). In contrast, memory B cells were resistant to the inhibitory effects of IL-4. Finally, the ability of human tonsillar CD4⁺CXCR5⁺CCR7^– T follicular helper (T_FH) cells, known to be a rich source of IL-21, to induce the differentiation of autologous B cells into ISC was mediated by the production of IL-21. These findings suggest that IL-21 produced by T_FH cells during the primary as well as the subsequent responses to T cell-dependent Ag makes a major contribution to eliciting and maintaining long-lived humoral immunity.

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. and K.L.G. were recipients of Postgraduate Research Awards from the University of Sydney. K.L.G. was the recipient of a Cancer Institute New South Wales Research Scholar Award. C.S.M., L.M.C., and S.G.T. are recipients of Research Fellowships awarded by the National Health and Medical Research Council. Schering Plough BioPharma is wholly funded by Schering Plough.

² Current address: Leonard Wagner Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, NY 10021.

³ Current address: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06510.

⁴ Address correspondence and reprint requests to Dr. Stuart Tangye, Immunology and Inflammation Department, 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: PC, plasma cells; AITL, angioimmunoblastic T-cell lymphoma; Blimp-1, B lymphocyte-induced maturation protein-1; CB, cord blood; GC, germinal center; ISC, Ig-secreting cell; PB, peripheral blood; T_FH, T follicular helper.

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