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J. Biol. Chem., Vol. 282, Issue 48, 34605-34610, November 30, 2007

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IL-21 Is Produced by Th17 Cells and Drives IL-17 Production in a STAT3-dependent Manner^*

Lai Wei¹, Arian Laurence, Kevin M. Elias², and John J. O'Shea

From the Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892 and Howard Hughes Medical Institute/National Institutes of Health Research Scholars Program, Bethesda, Maryland 20892

CD4⁺ helper T cells can differentiate into several possible fates including: Th1, Th2, T regulatory, and Th17 cells. Although, cytokine production by non-T cells is an important factor in helper T cell differentiation, a characteristic feature of both Th1 and Th2 lineages is their ability to secrete cytokines that promote their respective differentiation. However, cytokines produced by T cells that help to sustain Th17 cells have not yet been identified. Here we show that IL-21 is a product of Th17 cells, which is induced in a Stat3-dependent manner. Additionally, Stat3 can directly bind the Il21 promoter. IL-21 also induces IL-17 production and expression of the transcription factor, RORt. Furthermore, generation of Th17 cells in the conventional manner is attenuated by blocking IL-21. IL-21 is known to activate Stat3 and its ability to induce Th17 differentiation is abrogated in the absence of Stat3. These data argue that IL-21 serves as an autocrine factor secreted by Th17 cells that promotes or sustains Th17 lineage commitment.

Received for publication, June 21, 2007 , and in revised form, August 3, 2007.

^* 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.

² Howard Hughes Medical Institute/National Institutes of Health Research Scholar.

¹ Supported by National Research Council Research Associate fellowship. To whom correspondence should be addressed: National Institutes of Health, 10 Center Dr., 9N256, Bethesda, MD 20892. Ph.: 301-402-5133; Fax: 301-402-0012; E-mail: weil2{at}mail.nih.gov.

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