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* Research Institute for Biological Sciences, Tokyo University of Science, Yamazaki, Noda City, Chiba, Japan;
Research and Development Division, Mitsubishi Pharma, Aoba-ku, Yokohama, Japan;
Department of Molecular Embryology, Research Institute Osaka Medical Center for Maternal and Child Health, Izumi-shi, Osaka, Japan;
Division of Medical Biochemistry, Department of Biomolecular Sciences, and
¶ Division of Medical Research, Center for Comprehensive Community Medicine, Saga Medical School, Saga, Japan;
|| Division of Immunology, University of Cape Town, Groote Schuur Hospital, Cape Town, South Africa; and
# Signal/Network Team, RIKEN Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Suehiro-cho, Tsurumi, Yokohama, Kanagawa, Japan
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-4
R-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.
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