Ataxia-telangiectasia (A-T) is a multisystem disorder caused by biallelic pathogenic variants in the gene encoding A-T mutated (ATM) kinase, a master regulator of the DNA damage response (DDR) pathway. Most A-T patients show cellular and/or humoral immunodeficiency that has been associated with cancer risk and reduced survival, but NK cells have not been thoroughly studied. Here we investigated NK cells of A-T patients with a special focus on the NKG2D receptor that triggers cytotoxicity upon engagement by its ligands (NKG2DLs) commonly induced via the DDR pathway on infected, transformed, and variously stressed cells.

Using flow cytometry, we examined the phenotype and function of NK cells in 6 A-T patients as compared with healthy individuals. NKG2D expression was evaluated also by western blotting and RT-qPCR; plasma soluble NKG2DLs (sMICA, sMICB, sULBP1, ULBP2) were measured by ELISA.

Results showed that A-T NK cells were skewed towards the CD56^neg anergic phenotype and displayed decreased expression of NKG2D and perforin. NKG2D was reduced at the protein but not at the mRNA level and resulted in impaired NKG2D-mediated cytotoxicity in 4/6 A-T patients. Moreover, in A-T plasma we found 24-fold and 2-fold increase of sMICA and sULBP1, respectively, both inversely correlated with NKG2D expression.

Overall, NK cells are disturbed in A-T patients showing reduced NKG2D expression, possibly caused by persistent engagement of its ligands, that may contribute to susceptibility to cancer and infections and represent novel targets for therapeutic interventions.

共济失调毛细血管扩张症 (AT) 是一种多系统疾病，由编码 AT 突变 (ATM) 激酶的基因中的双等位基因致病变异引起，AT 突变 (ATM) 激酶是 DNA 损伤反应 (DDR) 通路的主要调节因子。大多数 AT 患者表现出与癌症风险和存活率降低相关的细胞和/或体液免疫缺陷，但尚未对 NK 细胞进行彻底研究。在这里，我们研究了 AT 患者的 NK 细胞，特别关注 NKG2D 受体，该受体在其配体 (NKG2DL) 参与时触发细胞毒性，通常通过 DDR 途径对感染、转化和各种应激细胞进行诱导。

使用流式细胞术，我们检查了 6 名 AT 患者与健康个体相比 NK 细胞的表型和功能。NKG2D 表达也通过蛋白质印迹和 RT-qPCR 进行评估；通过ELISA测量血浆可溶性NKG2DL（sMICA、sMICB、sULBP1、ULBP2）。

结果表明，AT NK 细胞倾向于 CD56^阴性无能表型，并显示出 NKG2D 和穿孔素的表达降低。NKG2D 在蛋白质水平而非 mRNA 水平上减少，并导致 4/6 AT 患者的 NKG2D 介导的细胞毒性受损。此外，在 AT 血浆中，我们发现 sMICA 和 sULBP1 分别增加了 24 倍和 2 倍，均与 NKG2D 表达呈负相关。

总体而言，在 AT 患者中 NK 细胞受到干扰，显示出 NKG2D 表达降低，这可能是由于其配体的持续参与引起的，这可能有助于对癌症和感染的易感性，并代表治疗干预的新目标。