Immunity ( IF 25.5 ) Pub Date : 2018-05-29 , DOI: 10.1016/j.immuni.2018.04.018
Nicholas M Adams 1 , Colleen M Lau 2 , Xiying Fan 2 , Moritz Rapp 2 , Clair D Geary 2 , Orr-El Weizman 2 , Carlos Diaz-Salazar 2 , Joseph C Sun 3
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Natural killer (NK) cells are innate lymphocytes that display features of adaptive immunity during viral infection. Biallelic mutations in IRF8 have been reported to cause familial NK cell deficiency and susceptibility to severe viral infection in humans; however, the precise role of this transcription factor in regulating NK cell function remains unknown. Here, we show that cell-intrinsic IRF8 was required for NK-cell-mediated protection against mouse cytomegalovirus infection. During viral exposure, NK cells upregulated IRF8 through interleukin-12 (IL-12) signaling and the transcription factor STAT4, which promoted epigenetic remodeling of the Irf8 locus. Moreover, IRF8 facilitated the proliferative burst of virus-specific NK cells by promoting expression of cell-cycle genes and directly controlling Zbtb32, a master regulator of virus-driven NK cell proliferation. These findings identify the function and cell-type-specific regulation of IRF8 in NK-cell-mediated antiviral immunity and provide a mechanistic understanding of viral susceptibility in patients with IRF8 mutations.
中文翻译:
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转录因子 IRF8 协调适应性自然杀伤细胞反应
自然杀伤 (NK) 细胞是先天性淋巴细胞,在病毒感染过程中表现出适应性免疫的特征。据报道,IRF8 中的双等位基因突变会导致人类家族性 NK 细胞缺乏和对严重病毒感染的易感性;然而,这种转录因子在调节 NK 细胞功能中的确切作用仍然未知。在这里,我们表明细胞内在的 IRF8 是 NK 细胞介导的对小鼠巨细胞病毒感染的保护所必需的。在病毒暴露期间,NK 细胞通过白细胞介素 12 (IL-12) 信号传导和转录因子 STAT4 上调 IRF8,从而促进 Irf8 基因座的表观遗传重塑。此外,IRF8 通过促进细胞周期基因的表达和直接控制病毒驱动的 NK 细胞增殖的主要调节因子 Zbtb32 来促进病毒特异性 NK 细胞的增殖爆发。这些发现确定了 IRF8 在 NK 细胞介导的抗病毒免疫中的功能和细胞类型特异性调节,并为 IRF8 突变患者的病毒易感性提供了机制理解。