Leukocyte Immunoglobulin-Like Receptor 1-Expressing Human Natural Killer Cell Subsets Differentially Recognize Isolates of Human Cytomegalovirus through the Viral Major Histocompatibility Complex Class I Homolog UL18.
Leukocyte Immunoglobulin-Like Receptor 1-Expressing Human Natural Killer Cell Subsets Differentially Recognize Isolates of Human Cytomegalovirus through the Viral Major Histocompatibility Complex Class I Homolog UL18.
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DOI：
10.1128/jvi.02614-15
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发表时间：
2016-01-06
影响因子：
5.4
通讯作者：
Wills MR
中科院分区：
文献类型：
--
作者：
Chen KC;Stanton RJ;Banat JJ;Wills MR
自然杀伤（NK）细胞的免疫应答受激活和抑制受体之间的平衡控制，但这些受体的表达在个体内的细胞之间存在差异。尽管NK细胞是先天免疫系统的一个组成部分，但表达Ly 49 H的特定NK细胞亚群在小鼠中响应于巨细胞病毒感染而被积极选择并频率增加。最近的证据表明，在人类中，某些NK亚群在人巨细胞病毒（HCMV）感染个体的血液中也具有增加的频率。然而，这些亚群是否在其直接控制HCMV感染细胞的能力方面存在差异仍不清楚。在这项研究中，我们开发了一种新的体外试验，以评估人类NK细胞亚群是否具有不同的能力，以抑制HCMV的生长和传播。表达或缺乏NKG 2C的NK细胞在控制病毒传播方面没有表现出任何差异。然而，当使用体外扩增的NK细胞时，表达或缺乏抑制性受体白细胞免疫球蛋白样受体1（LIR 1）的细胞能够差异地控制传播。令人惊讶的是，LIR 1 + NK细胞控制病毒传播的能力在HCMV病毒株之间存在差异，并且这种现象取决于病毒配体UL 18内的氨基酸序列。总之，这里的结果概述了一种体外技术，比较不同的人NK细胞亚群的长期免疫应答，并首次表明，表型定义的人NK细胞亚群可能差异识别HCMV感染。重要性HCMV感染在大多数人群中普遍存在;它在初次感染后不能被宿主清除，而是终身存在。先天性和适应性免疫系统控制病毒的传播，其中自然杀伤（NK）细胞发挥着关键作用。NK细胞可以通过快速、短期、非特异性的先天性应答对HCMV感染作出应答，但来自小鼠研究的证据表明，NK细胞可能对小鼠巨细胞病毒感染表现出长期、记忆样应答。在这项研究中，我们开发了一种新的检测方法，检测人类NK细胞亚群，这些亚群被认为对HCMV感染起着长期记忆样反应。我们发现，与NK细胞受体相互作用的HCMV病毒蛋白的变化可以改变NK细胞亚群控制HCMV的能力，而另一种受体的获得对病毒控制没有影响。
Immune responses of natural killer (NK) cell are controlled by the balance between activating and inhibitory receptors, but the expression of these receptors varies between cells within an individual. Although NK cells are a component of the innate immune system, particular NK cell subsets expressing Ly49H are positively selected and increase in frequency in response to cytomegalovirus infection in mice. Recent evidence suggests that in humans certain NK subsets also have an increased frequency in the blood of human cytomegalovirus (HCMV)-infected individuals. However, whether these subsets differ in their capacity of direct control of HCMV-infected cells remains unclear. In this study, we developed a novel in vitro assay to assess whether human NK cell subsets have differential abilities to inhibit HCMV growth and dissemination. NK cells expressing or lacking NKG2C did not display any differences in controlling viral dissemination. However, when in vitro-expanded NK cells were used, cells expressing or lacking the inhibitory receptor leukocyte immunoglobulin-like receptor 1 (LIR1) were differentially able to control dissemination. Surprisingly, the ability of LIR1+ NK cells to control virus spread differed between HCMV viral strains, and this phenomenon was dependent on amino acid sequences within the viral ligand UL18. Together, the results here outline an in vitro technique to compare the long-term immune responses of different human NK cell subsets and suggest, for the first time, that phenotypically defined human NK cell subsets may differentially recognize HCMV infections. IMPORTANCE HCMV infection is ubiquitous in most populations; it is not cleared by the host after primary infection but persists for life. The innate and adaptive immune systems control the spread of virus, for which natural killer (NK) cells play a pivotal role. NK cells can respond to HCMV infection by rapid, short-term, nonspecific innate responses, but evidence from murine studies suggested that NK cells may display long-term, memory-like responses to murine cytomegalovirus infection. In this study, we developed a new assay that examines human NK cell subsets that have been suggested to play a long-term memory-like response to HCMV infection. We show that changes in an HCMV viral protein that interacts with an NK cell receptor can change the ability of NK cell subsets to control HCMV while the acquisition of another receptor has no effect on virus control.