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The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor

机译：DNA损伤途径调节NKG2D受体的先天免疫系统配体

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摘要

Some stimulatory receptors of the innate immune system, such as the NKG2D receptor ( also called KLRK1) expressed by natural killer cells and activated CD8(+) T cells, recognize self-molecules that are upregulated in diseased cells by poorly understood mechanisms(1). Here we show that mouse and human NKG2D ligands are upregulated in non-tumour cell lines by genotoxic stress and stalled DNA replication, conditions known to activate a major DNA damage checkpoint pathway initiated by ATM ( ataxia telangiectasia, mutated) or ATR (ATM- and Rad3-related) protein kinases(2). Ligand upregulation was prevented by pharmacological or genetic inhibition of ATR, ATM or Chk1 ( a downstream transducer kinase in the pathway). Furthermore, constitutive ligand expression by a tumour cell line was inhibited by targeting short interfering RNA to ATM, suggesting that ligand expression in established tumour cells, which often harbour genomic irregularities, may be due to chronic activation of the DNA damage response pathway. Thus, the DNA damage response, previously shown to arrest the cell cycle and enhance DNA repair functions, or to trigger apoptosis, may also participate in alerting the immune system to the presence of potentially dangerous cells.
机译：先天性免疫系统的某些刺激性受体，例如由自然杀伤细胞和活化的CD8（+）T细胞表达的NKG2D受体（也称为KLRK1），会通过对机制的了解不清而识别在疾病细胞中上调的自身分子（1）。 。在这里，我们显示了小鼠和人类NKG2D配体在非肿瘤细胞系中受到基因毒性压力和停滞的DNA复制（已知激活ATM（共济失调毛细血管扩张，突变）或ATR（ATM和Rad3相关蛋白激酶（2）。通过药理学或遗传学上的抑制ATR，ATM或Chk1（途径中的下游转导激酶）来防止配体上调。此外，通过将短干扰RNA靶向ATM来抑制肿瘤细胞系的组成性配体表达，这表明已建立的肿瘤细胞中的配体表达通常带有基因组不规则性，这可能是由于DNA损伤反应途径的长期激活所致。因此，先前显示出可以阻止细胞周期并增强DNA修复功能或触发细胞凋亡的DNA损伤反应，也可能参与提醒免疫系统存在潜在危险的细胞。

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