The basis for TCR-mediated regulation of the IL-2 receptor alpha chain gene: role of widely separated regulatory elements.

The interleukin-2 receptor alpha (IL-2Ralpha) chain is a component of high-affinity IL-2 receptors and thus is a key regulator of lymphocyte proliferation. Lineage-restricted and activation-dependent IL-2Ralpha transcription is controlled by four upstream positive regulatory regions (PRRs) and one downstream PRR. We now demonstrate that T-cell receptor (TCR) responsiveness requires both upstream sequences and an intronic region, PRRIV, previously identified as an IL-2 response element. Whereas IL-2 responsiveness requires Stat5 and HMG-I(Y) binding, TCR responsiveness of PRRIV requires two AP-1- and two NFAT-binding sites that bind Jun, Fos and NFAT family members in vitro and in vivo. Moreover, IL-2Ralpha induction is impaired in T lymphocytes from transgenic mice expressing a dominant-negative c-jun construct, or following treatment with cyclosporin A. Thus, our data indicate an important role for both AP-1 and NFAT proteins for TCR-induced IL-2Ralpha expression and establish that both upstream and intronic sequences mediate TCR responsiveness of the IL-2Ralpha gene. Moreover, our data reveal a previously unappreciated link between the TCR-mediated up-regulation of the IL-2 and IL-2Ralpha genes.