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.
Kim
Hyoung-Pyo
HP
Laboratory of Molecular Immunology, Building 10, Room 7N252, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. hpkim@helix.nih.gov
Leonard
Warren J
WJ
D000818:Animals; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005809:Genes, Regulator / Q000235:genetics*; D017930:Genes, Reporter; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D016755:Proto-Oncogene Proteins c-jun; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D016572:Cyclosporine