BACKGROUND Natural killer (NK) cells are critical innate effector cells whose development is dependent on the Janus kinase-signal transducer and activator of transcription (STAT) pathway. NK cell deficiency can result in severe or refractory viral infections. Patients with STAT1 gain-of-function (GOF) mutations have increased viral susceptibility. OBJECTIVE We sought to investigate NK cell function in patients with STAT1 GOF mutations. METHODS NK cell phenotype and function were determined in 16 patients with STAT1 GOF mutations. NK cell lines expressing patients' mutations were generated with clustered regularly interspaced short palindromic repeats (CRISPR-Cas9)-mediated gene editing. NK cells from patients with STAT1 GOF mutations were treated in vitro with ruxolitinib. RESULTS Peripheral blood NK cells from patients with STAT1 GOF mutations had impaired terminal maturation. Specifically, patients with STAT1 GOF mutations have immature CD56dim NK cells with decreased expression of CD16, perforin, CD57, and impaired cytolytic function. STAT1 phosphorylation was increased, but STAT5 was aberrantly phosphorylated in response to IL-2 stimulation. Upstream inhibition of STAT1 signaling with the small-molecule Janus kinase 1/2 inhibitor ruxolitinib in vitro and in vivo restored perforin expression in CD56dim NK cells and partially restored NK cell cytotoxic function. CONCLUSIONS Properly regulated STAT1 signaling is critical for NK cell maturation and function. Modulation of increased STAT1 phosphorylation with ruxolitinib is an important option for therapeutic intervention in patients with STAT1 GOF mutations.

中文翻译：

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Ruxolitinib 部分逆转了信号转导和转录激活因子 1 (STAT1) 功能获得性突变患者的功能性自然杀伤细胞缺陷。

背景自然杀伤 (NK) 细胞是关键的先天效应细胞，其发育依赖于 Janus 激酶信号转导和转录激活因子 (STAT) 通路。NK 细胞缺乏可导致严重或难治性病毒感染。STAT1 功能获得性 (GOF) 突变患者的病毒易感性增加。目的 我们试图调查 STAT1 GOF 突变患者的 NK 细胞功能。方法 确定 16 例 STAT1 GOF 突变患者的 NK 细胞表型和功能。表达患者突变的 NK 细胞系是通过成簇的规则间隔短回文重复序列 (CRISPR-Cas9) 介导的基因编辑生成的。来自具有 STAT1 GOF 突变的患者的 NK 细胞在体外用鲁索替尼进行治疗。结果 STAT1 GOF 突变患者的外周血 NK 细胞终末成熟受损。具体而言，STAT1 GOF 突变患者的 CD56dim NK 细胞未成熟，CD16、穿孔素、CD57 表达降低，细胞溶解功能受损。STAT1 磷酸化增加，但 STAT5 响应 IL-2 刺激异常磷酸化。在体外和体内，使用小分子 Janus 激酶 1/2 抑制剂鲁索替尼对 STAT1 信号的上游抑制恢复了 CD56dim NK 细胞中穿孔素的表达，并部分恢复了 NK 细胞的细胞毒功能。结论 适当调节的 STAT1 信号对 NK 细胞的成熟和功能至关重要。用鲁索替尼调节增加的 STAT1 磷酸化是对 STAT1 GOF 突变患者进行治疗干预的重要选择。