Schulz Edda G, Mariani Luca, Radbruch Andreas, Höfer Thomas
Theoretical Biophysics, Institute of Biology, Humboldt Universität, Invalidenstrasse 42, 10115 Berlin, Germany.
Immunity. 2009 May;30(5):673-83. doi: 10.1016/j.immuni.2009.03.013. Epub 2009 Apr 30.
Differentiation of naive T lymphocytes into type I T helper (Th1) cells requires interferon-gamma and interleukin-12. It is puzzling that interferon-gamma induces the Th1 transcription factor T-bet, whereas interleukin-12 mediates Th1 cell lineage differentiation. We use mathematical modeling to analyze the expression kinetics of T-bet, interferon-gamma, and the IL-12 receptor beta2 chain (IL-12Rbeta2) during Th1 cell differentiation, in the presence or absence of interleukin-12 or interferon-gamma signaling. We show that interferon-gamma induced initial T-bet expression, whereas IL-12Rbeta2 was repressed by T cell receptor (TCR) signaling. The termination of TCR signaling permitted upregulation of IL-12Rbeta2 by T-bet and interleukin-12 signaling that maintained T-bet expression. This late expression of T-bet, accompanied by the upregulation of the transcription factors Runx3 and Hlx, was required to imprint the Th cell for interferon-gamma re-expression. Thus initial polarization and subsequent imprinting of Th1 cells are mediated by interlinked, sequentially acting positive feedback loops of TCR-interferon-gamma-Stat1-T-bet and interleukin-12-Stat4-T-bet signaling.
初始T淋巴细胞分化为I型辅助性T细胞（Th1）需要干扰素-γ和白细胞介素-12。令人困惑的是，干扰素-γ诱导Th1转录因子T-bet，而白细胞介素-12介导Th1细胞谱系分化。我们使用数学模型分析在存在或不存在白细胞介素-12或干扰素-γ信号的情况下，Th1细胞分化过程中T-bet、干扰素-γ和白细胞介素-12受体β2链（IL-12Rβ2）的表达动力学。我们发现干扰素-γ诱导初始T-bet表达，而IL-12Rβ2被T细胞受体（TCR）信号抑制。TCR信号的终止允许T-bet和白细胞介素-12信号上调IL-12Rβ2，从而维持T-bet表达。T-bet的这种晚期表达，伴随着转录因子Runx3和Hlx的上调，是Th细胞重新表达干扰素-γ所必需的。因此，Th1细胞的初始极化和随后的印记是由TCR-干扰素-γ-Stat1-T-bet和白细胞介素-12-Stat4-T-bet信号相互关联、顺序作用的正反馈回路介导的。
