Crucial role of DNA methylation in determination of clonally distributed killer cell Ig-like receptor expression patterns in NK cells
Crucial role of DNA methylation in determination of clonally distributed killer cell Ig-like receptor expression patterns in NK cells
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DOI：
10.4049/jimmunol.169.8.4253
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发表时间：
2002-10-15
影响因子：
4.4
通讯作者：
Uhrberg, M
中科院分区：
文献类型：
--
作者：
Santourlidis, S;Trompeter, HI;Uhrberg, M
人类NK细胞的特点是表达杀伤细胞igg样受体（KIR）家族的表面受体，参与对致病性靶细胞的特异性识别。每个NK细胞表达并维持一个单独的抑制性和刺激性KIR子集，并以这种方式促进NK细胞库的多样化。迄今为止，克隆分布的KIR表达模式产生的分子基础一直难以捉摸。在这里，对NK细胞系以及从外周血中新分离的NK细胞中KIR基因的DNA甲基化模式的分析表明，每个KIR基因转录起始位点周围的一个小CpG岛在表达的KIR中持续去甲基化，在未表达的KIR中持续甲基化。dna去甲基化处理导致NK细胞系、NK细胞克隆和新分离的NK细胞中所有先前未表达的KIR的转录和细胞表面表达的快速和稳定诱导，但在其他细胞类型中没有。KIR CpG岛的体外甲基化抑制NK细胞中报告基因的表达。我们得出结论，KIR克隆表达模式主要通过表观遗传决定并通过DNA甲基化维持。
Human NK cells are characterized by the expression of surface receptors of the killer cell Ig-like receptor (KIR) family, which are involved in the specific recognition of pathogenic target cells. Each NK cell expresses and maintains an individual subset of inhibitory and stimulatory KIR and in this way contributes to a diversified NK cell repertoire. To date, the molecular basis for generation of clonally distributed KIR expression patterns has been elusive. Here, analyses of DNA methylation patterns of KIR genes in NK cell lines as well as in NK cells, freshly isolated from peripheral blood, demonstrated that a small CpG island surrounding the transcriptional start site of each KIR gene is consistently demethylated in expressed KIR and methylated in unexpressed KIR. DNA-demethylating treatment resulted in a rapid and stable induction of transcription and cell surface expression of all formerly unexpressed KIR in NK cell lines, NK cell clones, and freshly isolated NK cells, but not in other cell types. In vitro methylation of KIR CpG islands repressed reporter gene expression in NK cells. We conclude that clonal patterns of KIR expression are mainly epigenetically determined and maintained through DNA methylation.