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Science 298 (5598): 1630-1634

Copyright © 2002 by the American Association for the Advancement of Science

A Critical Role for IL-21 in Regulating Immunoglobulin Production

Katsutoshi Ozaki,1* Rosanne Spolski,1 Carl G. Feng,2 Chen-Feng Qi,3 Jun Cheng,4 Alan Sher,2 Herbert C. Morse III,3 Chengyu Liu,5 Pamela L. Schwartzberg,4 Warren J. Leonard1dagger

The cytokine interleukin-21 (IL-21) is closely related to IL-2 and IL-15, and their receptors all share the common cytokine receptor gamma  chain, gamma c, which is mutated in humans with X-linked severe combined immunodeficiency disease (XSCID). We demonstrate that, although mice deficient in the receptor for IL-21 (IL-21R) have normal lymphoid development, after immunization, these animals have higher production of the immunoglobulin IgE, but lower IgG1, than wild-type animals. Mice lacking both IL-4 and IL-21R exhibited a significantly more pronounced phenotype, with dysgammaglobulinemia, characterized primarily by a severely impaired IgG response. Thus, IL-21 has a significant influence on the regulation of B cell function in vivo and cooperates with IL-4. This suggests that these gamma c-dependent cytokines may be those whose inactivation is primarily responsible for the B cell defect in humans with XSCID.

1 Laboratory of Molecular Immunology,
5 Transgenic Facility, National Heart, Lung, and Blood Institute,
2 Laboratory of Parasitic Disease,
3 Laboratory of Immunopathology, National Institute of Allergy and Infectious Disease,
4 Genetic Disease Research Branch, National Human Genome Research Institute, Building 49, Room 4A38, National Institutes of Health, Bethesda, MD 20892-1674, USA.
*   Present address: Institute of Medical Science, University of Tokyo, Tokyo, Japan.

dagger    To whom correspondence should be addressed. E-mail: wjl{at}

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Interleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities.
F. Eddahri, S. Denanglaire, F. Bureau, R. Spolski, W. J. Leonard, O. Leo, and F. Andris (2009)
Blood 113, 2426-2433
   Abstract »    Full Text »    PDF »
IL-21 Mediates Suppressive Effects via Its Induction of IL-10.
R. Spolski, H.-P. Kim, W. Zhu, D. E. Levy, and W. J. Leonard (2009)
J. Immunol. 182, 2859-2867
   Abstract »    Full Text »    PDF »
IL-21: An Executor of B Cell Fate.
D. Konforte, N. Simard, and C. J. Paige (2009)
J. Immunol. 182, 1781-1787
   Abstract »    Full Text »    PDF »
A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice.
J. A. Bubier, T. J. Sproule, O. Foreman, R. Spolski, D. J. Shaffer, H. C. Morse III, W. J. Leonard, and D. C. Roopenian (2009)
PNAS 106, 1518-1523
   Abstract »    Full Text »    PDF »
The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells.
O. Dienz, S. M. Eaton, J. P. Bond, W. Neveu, D. Moquin, R. Noubade, E. M. Briso, C. Charland, W. J. Leonard, G. Ciliberto, et al. (2009)
J. Exp. Med. 206, 69-78
   Abstract »    Full Text »    PDF »
Angiostatic activity of the antitumor cytokine interleukin-21.
K. Castermans, S. P. Tabruyn, R. Zeng, J. R. van Beijnum, C. Eppolito, W. J. Leonard, P. A. Shrikant, and A. W. Griffioen (2008)
Blood 112, 4940-4947
   Abstract »    Full Text »    PDF »
The IL-15 receptor {alpha} chain cytoplasmic domain is critical for normal IL-15R{alpha} function but is not required for trans-presentation.
Z. Wu, H.-H. Xue, J. Bernard, R. Zeng, D. Issakov, J. Bollenbacher-Reilley, I. M. Belyakov, S. Oh, J. A. Berzofsky, and W. J. Leonard (2008)
Blood 112, 4411-4419
   Abstract »    Full Text »    PDF »

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