Department of Medicine, Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Department of Medicine, Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine II: Gastroenterology, Hepatology, Endocrinology, and Infectious Disease, University Medical Center Freiburg, Freiburg, Germany.
Cell Mol Gastroenterol Hepatol. 2021;11(5):1267-1289. doi: 10.1016/j.jcmgh.2020.12.012. Epub 2021 Jan 11.
BACKGROUND & AIMS: Noroviruses (NoVs) are the leading cause of acute gastroenteritis worldwide and are associated with significant morbidity and mortality. Moreover, an asymptomatic carrier state can persist following acute infection, promoting NoV spread and evolution. Thus, defining immune correlates of NoV protection and persistence is needed to guide the development of future vaccines and limit viral spread. Whereas antibody responses following NoV infection or vaccination have been studied extensively, cellular immunity has received less attention. Data from the mouse NoV model suggest that T cells are critical for preventing persistence and achieving viral clearance, but little is known about NoV-specific T-cell immunity in humans, particularly at mucosal sites.
We screened peripheral blood mononuclear cells from 3 volunteers with an overlapping NoV peptide library. We then used HLA-peptide tetramers to track virus-specific CD8 T cells in peripheral, lymphoid, and intestinal tissues. Tetramer cells were further characterized using markers for cellular trafficking, exhaustion, cytotoxicity, and proliferation.
We defined 7 HLA-restricted immunodominant class I epitopes that were highly conserved across pandemic strains from genogroup II.4. NoV-specific CD8 T cells with central, effector, or tissue-resident memory phenotypes were present at all sites and were especially abundant in the intestinal lamina propria. The properties and differentiation states of tetramer cells varied across donors and epitopes.
Our findings are an important step toward defining the breadth, distribution, and properties of human NoV T-cell immunity. Moreover, the molecular tools we have developed can be used to evaluate future vaccines and engineer novel cellular therapeutics.
诺如病毒（NoV）是全世界急性肠胃炎的主要病因，与较高的发病率和死亡率相关。此外，急性感染后可能会持续无症状携带状态，从而促进 NoV 的传播和演变。因此，明确 NoV 保护和持续感染的免疫相关因素，对于指导未来疫苗的开发和限制病毒传播非常必要。尽管人们已经对 NoV 感染或接种疫苗后的抗体反应进行了广泛研究，但细胞免疫的关注度较低。来自鼠 NoV 模型的数据表明，T 细胞对于防止持续感染和实现病毒清除至关重要，但人们对人类的 NoV 特异性 T 细胞免疫知之甚少，尤其是在黏膜部位。
我们从 3 名志愿者的外周血单核细胞中筛选出了重叠的 NoV 肽库。然后，我们使用 HLA-肽四聚体来跟踪外周血、淋巴组织和肠道组织中的病毒特异性 CD8 T 细胞。使用细胞迁移、耗竭、细胞毒性和增殖的标志物进一步对四聚体细胞进行了特征描述。
我们定义了 7 个 HLA 限制的免疫优势 I 类表位，这些表位在来自基因型 II.4 的大流行株中高度保守。具有中央型、效应型或组织驻留记忆表型的 NoV 特异性 CD8 T 细胞存在于所有部位，并且在肠固有层中尤其丰富。四聚体细胞的特性和分化状态在不同供体和表位之间存在差异。
我们的研究结果是朝着定义人类 NoV T 细胞免疫的广度、分布和特性迈出的重要一步。此外，我们开发的分子工具可用于评估未来的疫苗并设计新型细胞治疗方法。
