Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Institute of Molecular Medicine "Angelo Nocivelli," University of Brescia, Brescia, Italy.
J Allergy Clin Immunol. 2017 Aug;140(2):553-564.e4. doi: 10.1016/j.jaci.2016.10.051. Epub 2017 Jan 6.
Gain-of-function (GOF) mutations affecting the coiled-coil domain or the DNA-binding domain of signal transducer and activator of transcription 1 (STAT1) cause chronic mucocutaneous candidiasis disease. This condition is characterized by fungal and bacterial infections caused by impaired generation of T17 cells; meanwhile, some patients with chronic mucocutaneous candidiasis disease might also have viral or intracellular pathogen infections.
We sought to investigate the effect of STAT1 GOF mutations on the functioning of natural killer (NK) cells.
Because STAT1 is involved in the signaling response to several cytokines, we studied NK cell functional activities and STAT1 signaling in 8 patients with STAT1 GOF mutations.
Functional analysis of NK cells shows a significant impairment of cytolytic and degranulation activities in patients with STAT1 GOF mutations. Moreover, NK cells from these patients display lower production of IFN-γ in response to IL-15 and reduced proliferation after stimulation with IL-2 or IL-15, suggesting that STAT5 signaling is affected. In addition, signaling studies demonstrate that the increased phosphorylation of STAT1 in response to IFN-α is associated with detectable activation of STAT1 and increased STAT1 binding to the interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) promoter in response to IL-15, whereas STAT5 phosphorylation and DNA binding to IL-2 receptor α (IL2RA) are reduced or not affected in response to the same cytokine.
These observations suggest that persistent activation of STAT1 might affect NK cell proliferation and functional activities.
影响信号转导子和转录激活子 1（STAT1）卷曲螺旋结构域或 DNA 结合结构域的获得性功能（GOF）突变会导致慢性黏膜皮肤念珠菌病。这种情况的特征是由于 T17 细胞生成受损而导致真菌感染和细菌感染；同时，一些慢性黏膜皮肤念珠菌病患者也可能存在病毒或细胞内病原体感染。
我们旨在研究 STAT1 GOF 突变对自然杀伤（NK）细胞功能的影响。
由于 STAT1 参与了几种细胞因子的信号反应，我们研究了 8 名 STAT1 GOF 突变患者的 NK 细胞功能活性和 STAT1 信号。
NK 细胞的功能分析显示，STAT1 GOF 突变患者的细胞毒性和脱颗粒活性显著受损。此外，这些患者的 NK 细胞在对 IL-15 的反应中产生的 IFN-γ 较少，并且在刺激后增殖减少IL-2 或 IL-15，表明 STAT5 信号受到影响。此外，信号研究表明，IFN-α 反应中 STAT1 磷酸化的增加与 STAT1 的可检测激活以及对 IL-15 的干扰素诱导蛋白具有四肽重复 1（IFIT1）启动子的 STAT1 结合增加有关，而 STAT5 磷酸化和 DNA 结合到 IL-2 受体α（IL2RA）则减少或不受相同细胞因子的影响。
这些观察结果表明，STAT1 的持续激活可能会影响 NK 细胞的增殖和功能活性。
