CpG methylation patterns in the IFNγ promoter in naive T cells:: Variations during Th1 and Th2 differentiation and between atopics and non-atopics
CpG methylation patterns in the IFNγ promoter in naive T cells:: Variations during Th1 and Th2 differentiation and between atopics and non-atopics
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DOI：
10.1111/j.1399-3038.2006.00465.x
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发表时间：
2006-12-01
影响因子：
4.4
通讯作者：
Holt, Patrick G.
中科院分区：
文献类型：
--
作者：
White, Gregory P.;Hollams, Elysia M.;Holt, Patrick G.
干扰素-γ（IFN-γ）基因表达在生命早期受到严格调控，CD 4（+）T细胞中IFN-γ产生的过度负控制与随后发生特应性的风险有关。最近的研究已经证明了新生儿IFN γ启动子中CpG位点的超甲基化，这是一种在小鼠中导致IFN γ基因转录强烈抑制的机制。在本研究中，6个CpG位点的甲基化状态的人IFN γ基因的近端启动子的亚硫酸氢盐测序确定。所研究的细胞群是来自新生儿和成人CD 4（+）/CD 45 RA（+）T细胞的Th 1或Th 2极化细胞系，来自儿童脐带血的CD 4（+）和CD 8（+）幼稚T细胞，以及来自6岁和成人特应性疾病和对照的CD 4（+）和CD 8（+）幼稚T细胞。我们证明，CD 4（+）T细胞沿着Th 1途径（但不是Th 2途径）的体外分化伴随着IFN γ启动子中CpG位点的进行性去甲基化，这在新生儿细胞中最为明显。2岁时特应性发育与脐带血T细胞甲基化模式的变化无关。然而，IFN γ启动子甲基化在来自该年龄段的特应性儿童的CD 8（+）T细胞中减少，其中IFN γ的过度产生最近被确定为特应性表型的共同特征。这些发现证明了IFN γ启动子甲基化作为控制人IFN γ基因表达的机制的效力，特别是在生命早期。T细胞中IFN γ启动子甲基化的差异调节可能是儿童期特应性发育的重要促成因素，这种可能性值得进一步详细研究。
Interferon-gamma (IFN gamma) gene expression is tightly regulated in early life, and exaggerated negative control of IFN gamma production in CD4(+) T cells has been associated with risk for subsequent development of atopy. Recent studies have demonstrated hypermethylation of CpG sites in the IFN gamma promoter in neonates, a mechanism which in mice leads to strong suppression of IFN gamma gene transcription. In the present study, the methylation status of six CpG sites in the proximal promoter of the human IFN gamma gene was determined by bisulphite sequencing. Cell populations studied were Th1 or Th2 polarized cell lines derived from neonatal and adult CD4(+)/CD45RA(+) T cells, CD4(+) and CD8(+) naive T cells from cord blood of children followed to outcome age 2 for assessment of atopy status, and CD4(+) and CD8(+) naive T cells from 6 yr old and adult atopics and controls. We demonstrate that in vitro differentiation of CD4(+) T cells down the Th1 pathway (but not the Th2 pathway) is accompanied by progressive demethylation of CpG sites in the IFN gamma promoter, which is most marked in neonatal cells. Atopy development by age 2 was not associated with variations in methylation patterns in cord blood T cells. However, IFN gamma promoter methylation was reduced in CD8(+) T cells from atopic children in the age range in which hyperproduction of IFN gamma as recently been identified as a common feature of the atopic phenotype. The findings demonstrate the potency of IFN gamma promoter methylation as a mechanism for control of human IFN gamma gene expression, particularly during early life. Differential regulation of IFN gamma promoter methylation in T cells may be an important contributory factor in atopy development in childhood, and this possibility warrants further detailed investigation.