Rapid demethylation of the IFN-γ gene occurs in memory but not naive CD8 T cells
Rapid demethylation of the IFN-γ gene occurs in memory but not naive CD8 T cells
复制标题
DOI：
10.4049/jimmunol.176.7.4083
复制
发表时间：
2006-04-01
影响因子：
4.4
通讯作者：
Ahmed, Rafi
中科院分区：
文献类型：
--
作者：
Kersh, Ellen N.;Fitzpatrick, David R.;Ahmed, Rafi
DNA甲基化是基因调控的一种表观遗传机制。我们已经确定，在体内记忆CD8 T细胞分化过程中，ifn - γ位点的DNA甲基化发生特异性修饰。抗病毒细胞因子ifn - γ在CD8 T细胞中的表达是高度发育阶段特异性的。大多数初始细胞必须先分裂才能表达IFN γ，而记忆细胞在细胞分裂前强烈表达IFN- γ。在病毒感染小鼠的过程中获得ag特异性CD8 T细胞，并直接在体外进行检测。幼稚细胞在三个特定的CpG位点有一个广泛甲基化的ifn - γ位点。一种甲基化抑制剂增加了初始细胞中ifn - γ的量，表明甲基化有助于ifn - γ缓慢而贫乏的产生。效应物未甲基化并产生大量ifn - γ。有趣的是，虽然记忆细胞也能够产生大量的ifn - γ，但该基因在三个CpG位点部分甲基化。然而，在抗原刺激的5小时内，该基因在记忆细胞中迅速去甲基化。这与DNA合成和细胞分裂无关，表明存在一种尚未确定的去甲基化酶。仅在记忆细胞中，酶促因子对ifn - γ启动子的快速去甲基化可能是一种新的差异基因调控机制。这种分化阶段特异性机制反映了一个基本的免疫学原理：幼稚细胞在成为有效的防御因子之前需要扩增，而已经增加前体频率的记忆细胞可以迅速发挥效应功能，以严格依赖ag的方式消除再感染的病原体。
DNA methylation is an epigenetic mechanism of gene regulation. We have determined that specific modifications in DNA methylation at the IFN-gamma locus occur during memory CD8 T cell differentiation in vivo. Expression of the antiviral cytokine IFN-gamma in CD8 T cells is highly developmental stage specific. Most naive cells must divide before they express IFN gamma, while memory cells vigorously express IFN-gamma before cell division. Ag-specific CD8 T cells were obtained during viral infection of mice and examined directly ex vivo. Naive cells had an IFN-gamma locus with extensive methylation at three specific CpG sites. An inhibitor of methylation increased the amount of IFN-gamma in naive cells, indicating that methylation contributes to the slow and meager production of IFN-gamma. Effectors were unmethylated and produced large amounts of IFN-gamma. Interestingly, while memory cells were also able to produce large amounts of IFN-gamma, the gene was partially methylated at the three CpG sites. Within 5 h of antigenic stimulation, however, the gene was rapidly demethylated in memory cells. This was independent of DNA synthesis and cell division, suggesting a yet unidentified demethylase. Rapid demethylation of the IFN-gamma promoter by an enzymatic factor only in memory cells would be a novel mechanism of differential gene regulation. This differentiation stage-specific mechanism reflects a basic immunologic principle: naive cells need to expand before becoming an effective defense factor, whereas memory cells with already increased precursor frequency can rapidly mount effector functions to eliminate reinfecting pathogens in a strictly Ag-dependent fashion.