Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine and The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
J Biol Chem. 2010 Jan 22;285(4):2545-53. doi: 10.1074/jbc.M109.038794. Epub 2009 Nov 18.
CD4+ T cells can be instructed by nonantigen-specific signals to differentiate into functionally distinct lineages with mutually exclusive patterns of cytokine production. The molecular events that drive interferon-gamma (IFN gamma) production during Th1 development are well understood, but mechanisms that silence this cytokine during Th2 polarization are not clear. In this study, we find that the tbx21 gene encoding the Th1 master regulator T-bet is a direct target of the transcriptional repressor Ikaros. In Th2 cells, which do not express T-bet, strong Ikaros binding could be detected at the endogenous tbx21 promoter, whereas this gene was not occupied by Ikaros in T-bet-expressing Th1 cells. Inhibition of Ikaros DNA binding activity during Th2 polarization resulted in loss of Ikaros promoter occupancy, increased T-bet expression, and inappropriate T-bet-dependent production of IFN gamma. Ikaros was also required for epigenetic imprinting of the ifn gamma locus during Th2 polarization, and loss of Ikaros function in vivo led to an inappropriate Th1 response to the parasite Shistosoma mansoni. These studies demonstrate that Ikaros, a factor with an established role in lymphocyte development, also regulates the development of peripheral T helper responses.
CD4+ T 细胞可以通过非抗原特异性信号指导分化为具有相互排斥的细胞因子产生模式的功能不同的谱系。在 Th1 发育过程中驱动干扰素-γ（IFNγ）产生的分子事件已得到很好的理解，但是在 Th2 极化过程中使该细胞因子沉默的机制尚不清楚。在这项研究中，我们发现编码 Th1 主调控因子 T-bet 的 tbx21 基因是转录抑制因子 Ikaros 的直接靶标。在不表达 T-bet 的 Th2 细胞中，可以在内源性 tbx21 启动子上检测到强的 Ikaros 结合，而在表达 T-bet 的 Th1 细胞中，该基因未被 Ikaros 占据。在 Th2 极化过程中抑制 Ikaros DNA 结合活性导致 Ikaros 启动子占据的丧失，T-bet 表达增加以及不适当的 T-bet 依赖性 IFNγ产生。Ikaros 还需要在 Th2 极化过程中对 ifnγ 基因座进行表观遗传印迹，并且体内 Ikaros 功能的丧失导致对寄生虫曼氏血吸虫的不适当 Th1 反应。这些研究表明，Ikaros，一种在淋巴细胞发育中具有既定作用的因子，也调节外周 T 辅助反应的发育。
