Tyrosine kinase 2 is not limiting human antiviral type III interferon responses
Tyrosine kinase 2 is not limiting human antiviral type III interferon responses
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DOI：
10.1002/eji.201646519
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发表时间：
2016-11-01
影响因子：
5.4
通讯作者：
Ehl, Stephan
中科院分区：
文献类型：
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作者：
Fuchs, Sebastian;Kaiser-Labusch, Petra;Ehl, Stephan
酪氨酸激酶2 （TYK2）与干扰素(IFN) α受体、IL-10受体(IL-10R) β和其他细胞因子受体亚基结合，参与信号转导，响应各种细胞因子，包括i型和iii型IFN、IL-6、IL-10、IL-12和IL-23。关于TYK2对细胞因子反应的依赖性和TYK2缺乏的体内后果的数据不一致。我们研究了一名TYK2缺乏的患者，表现为湿疹、皮肤脓肿、呼吸道感染和IgE水平bb0 1000 U/mL，没有病毒或分枝杆菌感染，并建立了相应的细胞模型来分析TYK2在iii型IFN介导的反应和nk细胞功能中的作用。我们建立了一种新的简单诊断单核细胞试验，表明突变完全消除了ifn - α介导的抗病毒反应。它也部分减少IL-10，但不减少IL-6介导的与IL-10R β表达减少相关的信号。然而，我们发现在TYK2缺陷的人类细胞系中，几乎正常的iii型IFN信号与病毒控制的最小损害相关。与TYK2缺陷小鼠的观察结果相反，患者的nk细胞表型和功能，包括IL-12/IL-18介导的反应，都是正常的。因此，保留的iii型IFN反应和正常的nk细胞功能可能有助于TYK2缺乏症的抗病毒保护，从而导致令人惊讶的轻度人类表型。
Tyrosine kinase 2 (TYK2) associates with interferon (IFN) alpha receptor, IL-10 receptor (IL-10R) beta and other cytokine receptor subunits for signal transduction, in response to various cytokines, including type-I and type-III IFNs, IL-6, IL-10, IL-12 and IL-23. Data on TYK2 dependence on cytokine responses and in vivo consequences of TYK2 deficiency are inconsistent. We investigated a TYK2 deficient patient, presenting with eczema, skin abscesses, respiratory infections and IgE levels >1000 U/mL, without viral or mycobacterial infections and a corresponding cellular model to analyze the role of TYK2 in type-III IFN mediated responses and NK-cell function. We established a novel simple diagnostic monocyte assay to show that the mutation completely abolishes the IFN-alpha mediated antiviral response. It also partly reduces IL-10 but not IL-6 mediated signaling associated with reduced IL-10R beta expression. However, we found almost normal type-III IFN signaling associated with minimal impairment of virus control in a TYK2 deficient human cell line. Contrary to observations in TYK2 deficient mice, NK-cell phenotype and function, including IL-12/IL-18 mediated responses, were normal in the patient. Thus, preserved type-III IFN responses and normal NK-cell function may contribute to antiviral protection in TYK2 deficiency leading to a surprisingly mild human phenotype.