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

TY - JOUR

T1 - IL-4-induced GATA-3 expression is a time-restricted instruction switch for Th2 cell differentiation

AU - Seki, Noriyasu

AU - Miyazaki, Mayumi

AU - Suzuki, Wataru

AU - Hayashi, Katsuhiko

AU - Arima, Kazuhiko

AU - Myburgh, Elmarie

AU - Izuhara, Kenji

AU - Brombacher, Frank

AU - Kubo, Masato

PY - 2004/5/15

Y1 - 2004/5/15

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Differentiation/genetics

KW - Cell Division/genetics

KW - Cell Line

KW - Cell Lineage/genetics

KW - Cell Separation

KW - Chromatin/metabolism

KW - Conserved Sequence

KW - GATA3 Transcription Factor

KW - Genetic Markers

KW - Humans

KW - Interleukin-4/biosynthesis

KW - Kinetics

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Knockout

KW - Mice, Transgenic

KW - Receptors, Interleukin-4/deficiency

KW - Signal Transduction/genetics

KW - Th2 Cells/cytology

KW - Transcription Factors/biosynthesis

U2 - 10.4049/jimmunol.172.10.6158

DO - 10.4049/jimmunol.172.10.6158

M3 - Article

C2 - 15128803

SN - 0022-1767

VL - 172

SP - 6158

EP - 6166

JO - Journal of Immunology

JF - Journal of Immunology

IS - 10

ER -