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Science 22 November 2002:
Vol. 298. no. 5598, pp. 1630 - 1634
DOI: 10.1126/science.1077002
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Reports

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}helix.nih.gov

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Distinct Activation Signals Determine whether IL-21 Induces B Cell Costimulation, Growth Arrest, or Bim-Dependent Apoptosis.
H. Jin, R. Carrio, A. Yu, and T. R. Malek (2004)
J. Immunol. 173, 657-665
   Abstract »    Full Text »    PDF »
The Size and Phenotype of Virus-Specific T Cell Populations Is Determined by Repetitive Antigenic Stimulation and Environmental Cytokines.
L. E. Gamadia, E. M. M. van Leeuwen, E. B. M. Remmerswaal, S.-L. Yong, S. Surachno, P. M. E. Wertheim-van Dillen, I. J. M. ten Berge, and R. A. W. van Lier (2004)
J. Immunol. 172, 6107-6114
   Abstract »    Full Text »    PDF »
Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation.
J. L. Roberts, A. Lengi, S. M. Brown, M. Chen, Y.-J. Zhou, J. J. O'Shea, and R. H. Buckley (2004)
Blood 103, 2009-2018
   Abstract »    Full Text »    PDF »
IL-21 Induces the Functional Maturation of Murine NK Cells.
J. Brady, Y. Hayakawa, M. J. Smyth, and S. L. Nutt (2004)
J. Immunol. 172, 2048-2058
   Abstract »    Full Text »    PDF »
IL-21 Induces Tumor Rejection by Specific CTL and IFN-{gamma}-Dependent CXC Chemokines in Syngeneic Mice.
E. Di Carlo, A. Comes, A. M. Orengo, O. Rosso, R. Meazza, P. Musiani, M. P. Colombo, and S. Ferrini (2004)
J. Immunol. 172, 1540-1547
   Abstract »    Full Text »    PDF »
In Vivo Antitumor Activity of Interleukin 21 Mediated by Natural Killer Cells.
G. Wang, M. Tschoi, R. Spolski, Y. Lou, K. Ozaki, C. Feng, G. Kim, W. J. Leonard, and P. Hwu (2003)
Cancer Res. 63, 9016-9022
   Abstract »    Full Text »    PDF »
Prevention of Organ Allograft Rejection by a Specific Janus Kinase 3 Inhibitor.
P. S. Changelian, M. E. Flanagan, D. J. Ball, C. R. Kent, K. S. Magnuson, W. H. Martin, B. J. Rizzuti, P. S. Sawyer, B. D. Perry, W. H. Brissette, et al. (2003)
Science 302, 875-878
   Abstract »    Full Text »    PDF »
IL-21 Activates Both Innate and Adaptive Immunity to Generate Potent Antitumor Responses that Require Perforin but Are Independent of IFN-{gamma}.
H.-L. Ma, M. J. Whitters, R. F. Konz, M. Senices, D. A. Young, M. J. Grusby, M. Collins, and K. Dunussi-Joannopoulos (2003)
J. Immunol. 171, 608-615
   Abstract »    Full Text »    PDF »
Characterization and Analysis of the Proximal Janus Kinase 3 Promoter.
M. Aringer, S. R. Hofmann, D. M. Frucht, M. Chen, M. Centola, A. Morinobu, R. Visconti, D. L. Kastner, J. S. Smolen, and J. J. O'Shea (2003)
J. Immunol. 170, 6057-6064
   Abstract »    Full Text »    PDF »


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