Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA.
Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, USA.
J Virol. 2018 Apr 27;92(10). doi: 10.1128/JVI.00014-18. Print 2018 May 15.
The mouse model of West Nile virus (WNV), which is a leading cause of mosquito-borne encephalitis worldwide, has provided fundamental insights into the host and viral factors that regulate viral pathogenesis and infection outcome. In particular, CD8 T cells are critical for controlling WNV replication and promoting protection against infection. Here, we present the characterization of a T cell receptor (TCR)-transgenic mouse with specificity for the immunodominant epitope in the WNV NS4B protein (here referred to as transgenic WNV-I mice). Using an adoptive-transfer model, we found that WNV-I CD8 T cells behave similarly to endogenous CD8 T cell responses, with an expansion phase in the periphery beginning around day 7 postinfection (p.i.) followed by a contraction phase through day 15 p.i. Through the use of intravascular immune cell staining, we determined the kinetics, expansion, and differentiation into effector and memory subsets of WNV-I CD8 T cells within the spleen and brain. We found that red-pulp WNV-I CD8 T cells were more effector-like than white-pulp WNV-I CD8 T cells, which displayed increased differentiation into memory precursor cells. Within the central nervous system (CNS), we found that WNV-I CD8 T cells were polyfunctional (gamma interferon [IFN-γ] and tumor necrosis factor alpha [TNF-α]), displayed tissue-resident characteristics (CD69 and CD103), persisted in the brain through day 15 p.i., and reduced the viral burden within the brain. The use of these TCR-transgenic WNV-I mice provides a new resource to dissect the immunological mechanisms of CD8 T cell-mediated protection during WNV infection. West Nile Virus (WNV) is the leading cause of mosquito-borne encephalitis worldwide. There are currently no approved therapeutics or vaccines for use in humans to treat or prevent WNV infection. CD8 T cells are critical for controlling WNV replication and protecting against infection. Here, we present a comprehensive characterization of a novel TCR-transgenic mouse with specificity for the immunodominant epitope in the WNV NS4B protein. In this study, we determine the kinetics, proliferation, differentiation into effector and memory subsets, homing, and clearance of WNV in the CNS. Our findings provide a new resource to dissect the immunological mechanisms of CD8 T cell-mediated protection during WNV infection.
西尼罗河病毒（WNV）是一种导致世界范围内蚊媒脑炎的主要病原体，其小鼠模型为研究宿主和病毒因素调节病毒发病机制和感染结果提供了重要的见解。特别是，CD8 T 细胞对于控制 WNV 复制和促进感染保护至关重要。在这里，我们介绍了一种针对 WNV NS4B 蛋白免疫优势表位的 T 细胞受体（TCR）转基因小鼠的特征（以下称为转基因 WNV-I 小鼠）。通过过继转移模型，我们发现 WNV-I CD8 T 细胞的行为类似于内源性 CD8 T 细胞反应，在感染后第 7 天左右开始在外周进行扩增阶段，然后在第 15 天通过收缩阶段。通过血管内免疫细胞染色，我们确定了 WNV-I CD8 T 细胞在脾和脑中的动力学、扩增和分化为效应和记忆亚群。我们发现红髓 WNV-I CD8 T 细胞比白髓 WNV-I CD8 T 细胞更具效应器样，后者显示出向记忆前体细胞分化的增加。在中枢神经系统（CNS）中，我们发现 WNV-I CD8 T 细胞具有多功能性（γ干扰素[IFN-γ]和肿瘤坏死因子α[TNF-α]），表现出组织驻留特性（CD69 和 CD103），在感染后第 15 天仍存在于大脑中，并降低了大脑中的病毒载量。使用这些 TCR 转基因 WNV-I 小鼠为剖析 CD8 T 细胞介导的 WNV 感染保护的免疫机制提供了新的资源。西尼罗河病毒（WNV）是世界范围内导致蚊媒脑炎的主要病原体。目前，尚无针对人类使用的批准的治疗或疫苗来治疗或预防 WNV 感染。CD8 T 细胞对于控制 WNV 复制和预防感染至关重要。在这里，我们介绍了一种针对 WNV NS4B 蛋白免疫优势表位的新型 TCR 转基因小鼠的全面特征。在这项研究中，我们确定了 WNV 在 CNS 中的动力学、增殖、分化为效应和记忆亚群、归巢和清除。我们的研究结果为剖析 WNV 感染期间 CD8 T 细胞介导的保护的免疫机制提供了新的资源。
