Cox Steven T, Pearson Hayley, Laza-Briviesca Raquel, Pesoa Susanna, Vullo Carlos, Madrigal J Alejandro, Saudemont Aurore
Anthony Nolan Research Institute, Royal Free Hospital, Hampstead, London NW3 2QU, UK.
Anthony Nolan Research Institute, Royal Free Hospital, Hampstead, London NW3 2QU, UK.
Hum Immunol. 2016 Jan;77(1):96-103. doi: 10.1016/j.humimm.2015.10.017. Epub 2015 Oct 28.
NKG2D is an activating receptor utilized by natural killer (NK) cells that recognizes upregulated ligands on infected, tumorigenic and damaged cells, leading to their cytolysis. However, the NKG2D ligand (NKG2DL) system is very complex with eight known gene loci encoding slightly different molecules. Furthermore, most NKG2DL gene loci such as MICA and MICB are highly polymorphic with potential for functional differences. NKG2DL expression on tumors varies depending on the malignancy and tumors can also release soluble NKG2DL that exert anergic effects on NK cells when engagement with NKG2D occurs, allowing escape from NK cell immunosurveillance. We carried out RAET1E typing of IHW cell line DNA, including a 580 bp proximal promoter fragment and exons 1-3 identifying 13 of 15 known RAET1E alleles. We determined 7 polymorphisms within the promoter region, including 2 already known that contributed to 9 promoter types. RAET1E alleles with variability in the extracellular region also differed with respect to promoter type and one allele, RAET1E(∗)003, associated with 5 promoter types. We then identified putative transcription factor binding sites for RAET1E, and found 5 of the 7 promoter polymorphisms may disrupt these sites, abrogating binding of transcription factors and varying the potential level of expression.
NKG2D是一种由自然杀伤（NK）细胞利用的激活受体，它识别受感染、致瘤和受损细胞上上调的配体，从而导致这些细胞的细胞溶解。然而，NKG2D配体（NKG2DL）系统非常复杂，有八个已知的基因座编码略有不同的分子。此外，大多数NKG2DL基因座，如MICA和MICB，具有高度多态性，存在功能差异的可能性。肿瘤上NKG2DL的表达因恶性程度而异，肿瘤还可释放可溶性NKG2DL，当与NKG2D结合时，其对NK细胞发挥无反应作用，从而使肿瘤细胞逃避NK细胞的免疫监视。我们对IHW细胞系DNA进行了RAET1E分型，包括一个580 bp的近端启动子片段和外显子1-3，确定了15个已知RAET1E等位基因中的13个。我们在启动子区域确定了7个多态性，其中包括2个已知的多态性，它们构成了9种启动子类型。细胞外区域具有变异性的RAET1E等位基因在启动子类型方面也存在差异，一个等位基因RAET1E(∗)003与5种启动子类型相关。然后我们确定了RAET1E的假定转录因子结合位点，发现7个启动子多态性中的5个可能会破坏这些位点，消除转录因子的结合并改变潜在的表达水平。
