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J. Biol. Chem., Vol. 280, Issue 40, 34042-34047, October 7, 2005

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Smad-dependent Cooperative Regulation of Interleukin 2 Receptor Chain Gene Expression by T Cell Receptor and Transforming Growth Factor-^*

Hyoung-Pyo Kim, Byung-Gyu Kim, John Letterio, and Warren J. Leonard1

From the Laboratory of Molecular Immunology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-1674 and the Laboratory of Cell Regulation and Carcinogenesis, NCI, Bethesda, Maryland 20892-5055

The interleukin 2 receptor chain (IL-2R) is a component of high affinity IL-2 receptors and thus critically regulates T cell growth and other lymphoid functions. Five positive regulatory regions together control lineage-restricted and activation-dependent IL-2R induction in response to antigen and IL-2. We now show that TGF- cooperates with T cell receptor (TCR) signaling to increase IL-2R gene expression. Moreover, we identify a sixth positive regulatory region that regulates IL-2R expression in cells treated with anti-CD3 + anti-CD28 as well as TGF- and show that this region contains binding sites for Smad3, AP-1, and cAMP-responsive element-binding protein/ATF proteins. The importance of Smad complexes is indicated by impaired IL-2R induction by TGF- in CD4⁺ T cells from both Smad3^-/- and Smad4^-/- mice. Thus, we have identified a novel positive regulatory region in the IL-2R gene that mediates TGF--dependent induction of the gene. These findings have implications related to IL-2R expression on activated T cells and regulatory T cells.

Received for publication, May 27, 2005 , and in revised form, August 2, 2005.

^* This work was supported by the Intramural Research Programs of the NHLBI and NCI of the National Institutes of Health. 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 To whom correspondence should be addressed: Laboratory of Molecular Immunology, Bldg. 10, Rm. 7N252, NHLBI, 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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