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J. Biol. Chem., Vol. 280, Issue 26, 25291-25297, July 1, 2005

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Calcium-dependent Activation of Interleukin-21 Gene Expression in T Cells^*

Hyoung-Pyo Kim, Lisa L. Korn, Ana M. Gamero, and Warren J. Leonard¶

From the Laboratory of Molecular Immunology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892 and the Laboratory of Experimental Immunology, NCI, National Institutes of Health, Frederick, Maryland 21702

Interleukin (IL)-21 is a _c-dependent cytokine produced by activated T cells with important actions for T, B, and NK cells. The IL-21 gene is adjacent to the IL-2 gene, and like IL-2, IL-21 is strongly induced at the transcriptional level after T cell activation. Interestingly, however, in contrast to the IL-2 gene, a calcium ionophore alone was sufficient to induce IL-21 gene expression in preactivated T cells. Two DNase I hypersensitivity sites were found in the IL-21 gene, corresponding to nucleotide sequences that are conserved in humans and mice. One site is located at the IL-21 promoter region and conferred T cell receptor-mediated IL-21 gene transcription. TCR-induced IL-21 gene expression was inhibited by cyclosporin A and FK506. Correspondingly, the IL-21 5'-regulatory region contains three NFAT binding sites, and induction of IL-21 promoter activity was impaired when these sites were mutated or following treatment with cyclosporin A. Thus, our studies reveal that in contrast to IL-2, a calcium signal alone is sufficient to mediate induction of the IL-21 in preactivated T lymphocytes and that this induction appears to result from specific NFAT binding.

Received for publication, February 8, 2005 , and in revised form, April 27, 2005.

^* 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.

^¶ To whom correspondence should be addressed: Laboratory of Molecular Immunology, Bldg. 10, Rm. 7N252, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892. Tel.: 301-496-0098; Fax: 301-402-0971; E-mail: wjl{at}helix.nih.gov.

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