Department of Molecular Medicine II and.
Institute of Virology, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
JCI Insight. 2019 Sep 5;4(17):129856. doi: 10.1172/jci.insight.129856.
`NK cell-mediated regulation of antigen-specific T cells can contribute to and exacerbate chronic viral infection, but the protective mechanisms against NK cell-mediated attack on T cell immunity are poorly understood. Here, we show that progranulin (PGRN) can reduce NK cell cytotoxicity through reduction of NK cell expansion, granzyme B transcription, and NK cell-mediated lysis of target cells. Following infection with the lymphocytic choriomeningitis virus (LCMV), PGRN levels increased - a phenomenon dependent on the presence of macrophages and type I IFN signaling. Absence of PGRN in mice (Grn-/-) resulted in enhanced NK cell activity, increased NK cell-mediated killing of antiviral T cells, reduced antiviral T cell immunity, and increased viral burden, culminating in increased liver immunopathology. Depletion of NK cells restored antiviral immunity and alleviated pathology during infection in Grn-/- mice. In turn, PGRN treatment improved antiviral T cell immunity. Taken together, we identified PGRN as a critical factor capable of reducing NK cell-mediated attack of antiviral T cells.
自然杀伤细胞介导的抗原特异性 T 细胞调节可导致并加重慢性病毒感染，但 NK 细胞介导的 T 细胞免疫攻击的保护机制尚不清楚。在这里，我们表明颗粒蛋白前体 (PGRN) 通过减少 NK 细胞的扩增、颗粒酶 B 的转录和 NK 细胞对靶细胞的溶解作用，降低 NK 细胞的细胞毒性。在感染淋巴细胞性脉络丛脑膜炎病毒 (LCMV) 后，PGRN 水平增加，这一现象依赖于巨噬细胞和 I 型 IFN 信号的存在。在没有 PGRN 的情况下，即 Grn-/- 小鼠中，NK 细胞活性增强，NK 细胞介导的抗病毒 T 细胞杀伤增加，抗病毒 T 细胞免疫降低，病毒载量增加，最终导致肝脏免疫病理学加重。在 Grn-/- 小鼠感染期间，NK 细胞耗竭恢复了抗病毒免疫并减轻了病理。反过来，PGRN 治疗改善了抗病毒 T 细胞免疫。综上所述，我们确定 PGRN 是一种能够降低 NK 细胞介导的抗病毒 T 细胞攻击的关键因素。
