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* Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia;
School of Biosciences, University of Birmingham, Edgbaston, United Kingdom; and
Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
The common 
-chain cytokine, IL-21, is produced by CD4+ T cells and mediates potent effects on a variety of immune cells including NK, T, and B cells. NKT cells express the receptor for IL-21; however, the effect of this cytokine on NKT cell function has not been studied. We show that IL-21 on its own enhances survival of NKT cells in vitro, and IL-21 increases the proliferation of NKT cells in combination with IL-2 or IL-15, and particularly with the CD1d-restricted glycosphingolipid Ag 
-galactosylceramide. Similar to its effects on NK cells, IL-21 enhances NKT cell granular morphology, including granzyme B expression, and some inhibitory NK receptors, including Ly49C/I and CD94. IL-21 also enhanced NKT cell cytokine production in response to anti-CD3/CD28 in vitro. Furthermore, NKT cells may be subject to autocrine IL-21-mediated stimulation because they are potent producers of this cytokine following in vitro stimulation via CD3 and CD28, particularly in conjunction with IL-12 or following in vivo stimulation with -galactosylceramide. Indeed, NKT cells produced much higher levels of IL-21 than conventional CD4 T cells in this assay. This study demonstrates that NKT cells are potentially a major source of IL-21, and that IL-21 may be an important factor in NKT cell-mediated immune regulation, both in its effects on NK, T, and B cells, as well as direct effects on NKT cells themselves. The influence of IL-21 in NKT cell-dependent models of tumor rejection, microbial clearance, autoimmunity, and allergy should be the subject of future investigations.
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 research grants from National Health and Medical Research Council of Australia, the National Institutes of Health, and The Association of International Cancer Research. J.M.C. is a recipient of a Cancer Research Institute Postgraduate Scholarship. D.I.G. and M.J.S. are recipients of National Health and Medical Research Council research fellowships.
2 Address correspondence and reprint requests to Dr. Dale I. Godfrey, Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia. E-mail address: godfrey{at}unimelb.edu.au
3 Abbreviations used in this paper: -GalCer, -galactosylceramide; 7-AAD, 7-aminoactinomycin D; DC, dendritic cell; c, common -chain.
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