IL-4-induced GATA-3 expression is a time-restricted instruction switch for Th2 cell differentiation

Noriyasu Seki, Mayumi Miyazaki, Wataru Suzuki, Katsuhiko Hayashi, Kazuhiko Arima, Elmarie Myburgh, Kenji Izuhara, Frank Brombacher, Masato Kubo

Research output: Contribution to journalArticlepeer-review


An initial activation signal via the TCR in a restricted cytokine environment is critical for the onset of Th cell development. Cytokines regulate the expression of key transcriptional factors, T-bet and GATA-3, which instruct the direction of Th1 and Th2 differentiation, through changes in chromatin conformation. In this study, we investigated the kinetics of IL-4-mediated signaling in a transgenic mouse, expressing human IL-4R on a mouse IL-4alphaR-deficient background. These experiments, allowing induction with human IL-4 at defined times, demonstrated that an IL-4 signal was required at the early stage of TCR-mediated T cell activation for lineage commitment to Th2, along with structural changes in chromatin, which take place in the conserved noncoding sequence-1 and -2 within the IL-4 locus. At later times, however, IL-4 failed to promote efficient Th2 differentiation and decondensation of chromatin, even though GATA-3 was clearly induced in the nuclei by IL-4 stimulation. Moreover, IL-4-mediated Th2 instruction was independent from cell division mediated by initial TCR stimulation. The role of IL-4 signaling may have a time restriction during Th2 differentiation. In late stages of initial T cell activation, the chromatin structure of the IL-4 locus retains condensation state. These results demonstrate that IL-4-induced GATA-3 expression is time-restriction switch for Th2 differentiation.

Original languageEnglish
Pages (from-to)6158-66
Number of pages9
JournalJournal of Immunology
Issue number10
Publication statusPublished - 15 May 2004


  • Animals
  • Cell Differentiation/genetics
  • Cell Division/genetics
  • Cell Line
  • Cell Lineage/genetics
  • Cell Separation
  • Chromatin/metabolism
  • Conserved Sequence
  • GATA3 Transcription Factor
  • Genetic Markers
  • Humans
  • Interleukin-4/biosynthesis
  • Kinetics
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, Transgenic
  • Receptors, Interleukin-4/deficiency
  • Signal Transduction/genetics
  • Th2 Cells/cytology
  • Transcription Factors/biosynthesis

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