DeWitt William S, Emerson Ryan O, Lindau Paul, Vignali Marissa, Snyder Thomas M, Desmarais Cindy, Sanders Catherine, Utsugi Heidi, Warren Edus H, McElrath Juliana, Makar Karen W, Wald Anna, Robins Harlan S
Adaptive Biotechnologies, Seattle, Washington, USA.
Fred Hutchinson Cancer Research Center, Seattle, Washington, USA University of Washington, Seattle, Washington, USA.
J Virol. 2015 Apr;89(8):4517-26. doi: 10.1128/JVI.03474-14. Epub 2015 Feb 4.
A detailed characterization of the dynamics and breadth of the immune response to an acute viral infection, as well as the determinants of recruitment to immunological memory, can greatly contribute to our basic understanding of the mechanics of the human immune system and can ultimately guide the design of effective vaccines. In addition to neutralizing antibodies, T cells have been shown to be critical for the effective resolution of acute viral infections. We report the first in-depth analysis of the dynamics of the CD8(+) T cell repertoire at the level of individual T cell clonal lineages upon vaccination of human volunteers with a single dose of YF-17D. This live attenuated yellow fever virus vaccine yields sterile, long-term immunity and has been previously used as a model to understand the immune response to a controlled acute viral infection. We identified and enumerated unique CD8(+) T cell clones specifically induced by this vaccine through a combined experimental and statistical approach that included high-throughput sequencing of the CDR3 variable region of the T cell receptor β-chain and an algorithm that detected significantly expanded T cell clones. This allowed us to establish that (i) on average, ∼ 2,000 CD8(+) T cell clones were induced by YF-17D, (ii) 5 to 6% of the responding clones were recruited to long-term memory 3 months postvaccination, (iii) the most highly expanded effector clones were preferentially recruited to the memory compartment, and (iv) a fraction of the YF-17D-induced clones could be identified from peripheral blood lymphocytes solely by measuring clonal expansion.
The exhaustive investigation of pathogen-induced effector T cells is essential to accurately quantify the dynamics of the human immune response. The yellow fever vaccine (YFV) has been broadly used as a model to understand how a controlled, self-resolving acute viral infection induces an effective and long-term protective immune response. Here, we extend this previous work by reporting the identity of activated effector T cell clones that expand in response to the YFV 2 weeks postvaccination (as defined by their unique T cell receptor gene sequence) and by tracking clones that enter the memory compartment 3 months postvaccination. This is the first study to use high-throughput sequencing of immune cells to characterize the breadth of the antiviral effector cell response and to determine the contribution of unique virus-induced clones to the long-lived memory T cell repertoire. Thus, this study establishes a benchmark against which future vaccines can be compared to predict their efficacy.
详细描述急性病毒感染免疫反应的动力学和广度，以及免疫记忆招募的决定因素，有助于我们深入理解人类免疫系统的机制，并最终指导有效疫苗的设计。除中和抗体外，T细胞对有效解决急性病毒感染至关重要。我们报告了首次对人类志愿者单剂量接种YF-17D疫苗后，在单个T细胞克隆谱系水平上对CD8(+) T细胞库动力学进行的深入分析。这种减毒活黄热病病毒疫苗可产生无菌的长期免疫力，此前一直被用作了解对可控急性病毒感染免疫反应的模型。我们通过一种综合实验和统计方法，包括对T细胞受体β链CDR3可变区的高通量测序以及检测显著扩增T细胞克隆的算法，鉴定并计数了该疫苗特异性诱导的独特CD8(+) T细胞克隆。这使我们能够确定：(i) 平均而言，YF-17D诱导约2000个CD8(+) T细胞克隆；(ii) 5%至6%的反应性克隆在接种疫苗后3个月被招募到长期记忆中；(iii) 扩增程度最高的效应性克隆优先被招募到记忆库中；(iv) 仅通过测量克隆扩增就可从外周血淋巴细胞中鉴定出一部分YF-17D诱导的克隆。
详尽研究病原体诱导的效应性T细胞对于准确量化人类免疫反应动力学至关重要。黄热病疫苗（YFV）已被广泛用作模型，以了解可控的、自我消退的急性病毒感染如何诱导有效且长期的保护性免疫反应。在此，我们通过报告接种疫苗后2周因YFV而扩增的活化效应性T细胞克隆的身份（由其独特的T细胞受体基因序列定义）以及追踪接种疫苗后3个月进入记忆库的克隆，扩展了先前的这项工作。这是第一项使用免疫细胞高通量测序来表征抗病毒效应细胞反应广度并确定独特病毒诱导克隆对长寿记忆T细胞库贡献的研究。因此，本研究建立了一个基准，可据此比较未来疫苗以预测其疗效。
