Smad-dependent cooperative regulation of interleukin 2 receptor α chain gene expression by T cell receptor and transforming growth factor-β

The interleukin 2 receptor alpha chain (IL-2R alpha) 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 alpha induction in response to antigen and IL-2. We now show that TGF-beta cooperates with T cell receptor (TCR) signaling to increase IL-2R alpha gene expression. Moreover, we identify a sixth positive regulatory region that regulates IL-2R alpha expression in cells treated with anti-CD3 + anti-CD28 as well as TGF-beta 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 alpha induction by TGF-beta in CD4(+) T cells from both Smad3(-/-) and Smad4(-/-) mice. Thus, we have identified a novel positive regulatory region in the IL-2R alpha gene that mediates TGF-beta-dependent induction of the gene. These findings have implications related to IL-2R alpha expression on activated T cells and regulatory T cells.