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

The interleukin-2 receptor α (IL-2Rα) 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-2Rα 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-2Rα 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-2Rα expression and establish that both upstream and intronic sequences mediate TCR responsiveness of the IL-2Rα gene. Moreover, our data reveal a previously unappreciated link between the TCR-mediated up-regulation of the IL-2 and IL-2Rα genes.