Interleukin-2 (IL-2) Regulates the Accessibility of the IL-2-Responsive Enhancer in the IL-2 Receptor α Gene to Transcription Factors

Abstract

Interleukin-2 (IL-2) responsiveness of T lymphocytes is controlled through transcription of the IL-2 receptor (IL-2R) α subunit by antigen and by IL-2 itself. IL-2 induces IL-2Rα transcription via an IL-2-responsive enhancer (IL-2rE), whose activity depends on the cooperative binding of IL-2-induced STAT5 to two sites and of constitutively active Elf-1 to a third one. Here we describe the changes in IL-2rE chromatin that occur in normal T lymphocytes upon activation of IL-2Rα expression. In cells induced to transiently express IL-2Rα with concanavalin A (which mimics antigen), none of the IL-2rE sites is occupied despite the presence of Elf-1 and STAT1, which bind to the IL-2rE in vitro. The two STAT binding sites are occupied rapidly upon IL-2 stimulation, concomitantly with STAT5 activation. Occupation of the Elf-1 binding site is delayed, although Elf-1 concentration and binding activity are not modified by IL-2. Digestion of T-cell chromatin with DNase I and micrococcal nuclease shows that IL-2 induces the appearance of nuclease-hypersensitive sites flanking the IL-2rE. Thus IL-2, in addition to activating STAT5, appears to regulate IL-2Rα transcription by making IL-2Rα chromatin accessible to transcription factors.

ACKNOWLEDGMENTS

We are grateful to Glaxo, Geneva, Switzerland, for the generous gift of IL-2. Jacques Louis, WHO, IRTC, Biochemistry Institute, Lausanne, Switzerland, kindly provided IFN-γR-deficient mice. Anne-Lise Peitrequin, Ludwig Institute, Lausanne, supplied us with the antibodies for the FACS analyses. We thank Jovan Mirkovitch, Jean Imbert, and Michèle Algarté for helpful technical advice and Véronique Imbert, Friedrich Beermann, and Moira Cockell for valuable discussions and advice during the preparation of the manuscript.

This work was supported, in part, by grants from the Swiss National Science Foundation, the Swiss Cancer League, and the Swiss Federal Office of Science and Technology.