IL-4-induced GATA-3 expression is a time-restricted instruction switch for Th2 cell differentiation.
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.
Seki
Noriyasu
N
Research Institute for Biological Sciences, Tokyo University of Science, Yamazaki, Noda City, Chiba, Japan.
Miyazaki
Mayumi
M
Suzuki
Wataru
W
Hayashi
Katsuhiko
K
Arima
Kazuhiko
K
Myburgh
Elmarie
E
Izuhara
Kenji
K
Brombacher
Frank
F
Kubo
Masato
M
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002469:Cell Separation; D002843:Chromatin / Q000378:metabolism; D017124:Conserved Sequence; D050990:GATA3 Transcription Factor; D005819:Genetic Markers; D006801:Humans; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019948:Receptors, Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D018418:Th2 Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
D002843:Chromatin; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D005819:Genetic Markers; D019948:Receptors, Interleukin-4; D014157:Transcription Factors; D015847:Interleukin-4