The human herpesvirus-7 (HHV-7) U21 immunoevasin subverts NK-mediated cytoxicity through modulation of MICA and MICB.
The human herpesvirus-7 (HHV-7) U21 immunoevasin subverts NK-mediated cytoxicity through modulation of MICA and MICB.
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DOI：
10.1371/journal.ppat.1002362
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发表时间：
2011-11
期刊：
影响因子：
6.7
通讯作者：
Hudson AW
中科院分区：
文献类型：
--
作者：
Schneider CL;Hudson AW
疱疹病毒已经进化出许多免疫逃避策略，以促进终生持续感染的建立。许多疱疹病毒编码专门用于阻止病毒抗原呈递的基因产物，作为逃避细胞毒性 T 淋巴细胞检测的手段。例如，人类疱疹病毒 7 (HHV-7) U21 基因产物是一种免疫逃避素，可与 I 类主要组织相容性复合体分子结合，并将其重定向至溶酶体区室。病毒感染还可诱导激活 NK 细胞的表面配体上调。因此，疱疹病毒已经进化出多种机制来阻止 NK 细胞与病毒感染细胞上的 NK 激活配体结合。在这里，我们证明 HHV-7 U21 基因产物干扰 NK 识别。 U21 可以与 NK 激活配体 ULBP1 结合，并将其重新路由至溶酶体区室。此外，U21 下调 NK 激活配体 MICA 和 MICB 的表面表达，从而减少 NK 介导的细胞毒性。这些结果表明，这种单一病毒蛋白可能通过下调 I 类 MHC 分子来干扰 CTL 介导的识别，也可能通过下调 NK 激活配体来干扰 NK 介导的识别。疱疹病毒与其宿主的长期共同进化导致了多种病毒免疫逃避策略和宿主对抗策略的发展。损害细胞免疫识别受体功能的病毒蛋白的鉴定已被证明为发现免疫学和细胞生物学基本概念奠定了沃土。虽然巨细胞病毒已表现出一系列非凡的免疫逃避策略，但人们对密切相关的人类疱疹病毒 7 (HHV-7) 的免疫逃避策略知之甚少。我们之前已经证明，HHV-7 的 U21 基因产物可能通过将 I 类主要组织相容性分子重新路由至溶酶体进行降解，从而干扰病毒抗原向细胞毒性 T 细胞的呈递。除了宿主的细胞毒性 T 细胞反应外，病毒感染还会诱导自然杀伤 (NK) 激活配体的表达，提醒细胞毒性 NK 细胞识别并杀死病毒感染的细胞。在这里，我们描述了同一病毒蛋白 U21 干扰 NK 细胞识别的新功能。我们的研究结果首次表明，HHV-7 可能也发现有必要制定 NK 逃逸机制的策略。
Herpesviruses have evolved numerous immune evasion strategies to facilitate establishment of lifelong persistent infections. Many herpesviruses encode gene products devoted to preventing viral antigen presentation as a means of escaping detection by cytotoxic T lymphocytes. The human herpesvirus-7 (HHV-7) U21 gene product, for example, is an immunoevasin that binds to class I major histocompatibility complex molecules and redirects them to the lysosomal compartment. Virus infection can also induce the upregulation of surface ligands that activate NK cells. Accordingly, the herpesviruses have evolved a diverse array of mechanisms to prevent NK cell engagement of NK-activating ligands on virus-infected cells. Here we demonstrate that the HHV-7 U21 gene product interferes with NK recognition. U21 can bind to the NK activating ligand ULBP1 and reroute it to the lysosomal compartment. In addition, U21 downregulates the surface expression of the NK activating ligands MICA and MICB, resulting in a reduction in NK-mediated cytotoxicity. These results suggest that this single viral protein may interfere both with CTL-mediated recognition through the downregulation of class I MHC molecules as well as NK-mediated recognition through downregulation of NK activating ligands. The long coevolution of herpesviruses with their hosts has resulted in the development of a diverse array of viral immune evasion strategies and host counter-strategies. The identification of viral proteins that impair the function of cellular immune-recognition receptors has proven fertile ground for the discovery of fundamental concepts in immunology and cell biology. While the cytomegaloviruses have demonstrated an extraordinary array of immunoevasive tactics, little is known about the immunoevasive strategies of the closely-related human herpesvirus-7 (HHV-7). We have previously demonstrated that the U21 gene product from HHV-7 likely interferes with viral antigen presentation to cytotoxic T cells by rerouting class I major histocompatibility molecules to lysosomes for degradation. In addition to the host's cytotoxic T cell response, virus infection also induces the expression of Natural-Killer (NK) activating ligands, alerting cytotoxic NK cells to identify and kill virus-infected cells. Here we describe a novel function for the same viral protein - U21 - in interfering with NK cell recognition. Our findings provide the first indication that HHV-7, too, may have found it necessary to strategize mechanisms of NK escape.
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DOI：
10.1084/jem.20021973
发表时间：
2003-05-19
期刊：
The Journal of experimental medicine
影响因子：
--
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Lodoen M;Ogasawara K;Hamerman JA;Arase H;Houchins JP;Mocarski ES;Lanier LL
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影响因子：
3.7
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DOI：
10.1073/pnas.91.14.6259
发表时间：
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DOI：
10.1073/pnas.0611655104
发表时间：
2007-04-10
影响因子：
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