Identification and characterization of effector memory B cell populations that dominate memory responses to subsequent influenza infection and vaccination

效应记忆 B 细胞群的鉴定和表征，该细胞群主导对随后流感感染和疫苗接种的记忆反应

• 批准号: 10455632
• 负责人: Frances E. Lund
• 金额: $ 73.54万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-03 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10455632
• 关键词: Adult; Animal Model; Antibodies; Antibody Response; Antibody-Producing Cells; Antigens; B-Lymphocyte Subsets; B-Lymphocytes; Biological Models; Blood; Cells; Clinical; Complex; Data; Development; Exposure to; Flu virus; Future; Goals; Healthcare; Human; Immune; Immune response; Immunity; Immunoglobulin-Secreting Cells; Individual; Infection; Inflammation; Influenza; Influenza Hemagglutinin; Influenza vaccination; Knowledge; Life; Link; Longevity; Lung; Lymphoid; Lymphoid Tissue; Mediator; Memory; Memory B-Lymphocyte; Morbidity - disease rate; Mucous Membrane; Mus; Persons; Population; Population Heterogeneity; Predictive Value; Public Health; Reaction; Seasons; Signal Transduction; Specificity; Structure of germinal center of lymph node; T memory cell; T-bet protein; Testing; Time; Tissues; Vaccination; Vaccines; Viral; Virus; antiviral immunity; cell type; cohort; cross reactivity; design; experimental study; flu; human tissue; imprint; improved; influenza infection; influenza virus vaccine; insight; mortality; new pandemic; novel vaccines; pandemic disease; pandemic virus; pressure; prevent; respiratory; response; seasonal influenza; tool; vaccine efficacy; vaccine response

Seasonal influenza (flu) infections kill hundreds of thousands of people throughout the world each year and morbidity and mortality rates increase even further when a new pandemic virus emerges. The annual flu vaccine provides an important line of defense against influenza infections but there are many documented examples of poor vaccine efficacy, even in healthy individuals. Thus, there is an unmet public health need to improve influenza vaccination. However, before we can improve the vaccine, we must first better understand the immune cells that respond to the vaccine. One cell type of particular importance is the memory B cell, which is rapidly recalled following infection and vaccination and can contribute to anti-viral immunity by differentiating into short-lived antibody secreting cells (ASCs) that produce antibodies (Ab) that can either neutralize the virus or facilitate its rapid clearance. Memory B cells also seed the vaccine-driven humoral immune response and can give rise to new cohorts of long-lived ASCs and memory B cells that will protect against future exposures to the circulating flu virus. Despite the fact that memory B cells are the direct targets of vaccination in adults, we know remarkably little about these cells. This substantial knowledge gap is due, at least in part, to an inability to isolate and characterize these cells. Studies of memory B cells in humans have been even more difficult as we can typically only look at the cells in the blood and many immune cells, including the memory B cells, reside in tissues that are usually inaccessible in humans. We developed new tools to track flu-specific memory B cells in both mice and humans and have now identified and characterized distinct populations in the tissues of mice that we believe are likely to contribute to long-lasting vaccine induced immune responses. The central hypothesis of this application is that a flu-specific memory B cell subset that expresses the transcription factor T-bet is maintained long-term in tissues like the lung and is preferentially recalled by vaccination. The specific goals for this proposal are to identify the vaccine-elicited signals required to establish lung-resident T-bet expressing memory B cells, to determine whether vaccination and infection induce distinct populations of memory B cell with differing functions and life- spans, to identify which memory B cell subsets are preferentially recalled following antigen exposure, and to evaluate whether the repertoire of the T-bet expressing memory B cells found in human tissues are enriched for reactivity to older “historic” flu antigens that the individual likely encountered early in life. The long term goal of this proposal is to fill our gap in our knowledge by developing the tools and animal model systems that will allow us to systematically and comprehensively study the heterogeneous populations of flu-specific memory B cells that persist in lymphoid and non-lymphoid tissues and are the direct targets of vaccination in adults. We believe that this contribution is significant as we expect to provide new insight into the complex and heterogeneous memory B compartment that is critical for vaccine-induced responses to flu.

季节性流感（流感）感染每年导致全世界数十万人死亡，当新的大流行病毒出现时，发病率和死亡率会进一步上升。每年一度的流感疫苗提供了抵御流感感染的重要防线，但有许多记录在案的疫苗效力不佳的例子，即使在健康个体中也是如此。因此，改善流感疫苗接种的公共卫生需求尚未得到满足。然而，在我们改进疫苗之前，我们必须首先更好地了解对疫苗产生反应的免疫细胞。其中一种特别重要的细胞类型是记忆 B 细胞，它在感染和接种疫苗后会被迅速召回，并可以通过分化为短寿命的抗体分泌细胞 (ASC) 来促进抗病毒免疫，这些细胞产生的抗体 (Ab) 可以中和病毒或促进其快速清除。记忆 B 细胞还能引发疫苗驱动的体液免疫反应，并能产生新的长寿 ASC 和记忆 B 细胞群，从而防止未来暴露于正在流行的流感病毒。尽管记忆 B 细胞是成人疫苗接种的直接目标，但我们对这些细胞知之甚少。这种巨大的知识差距至少部分是由于无法分离和表征这些细胞造成的。对人类记忆 B 细胞的研究更加困难，因为我们通常只能观察血液中的细胞，而许多免疫细胞（包括记忆 B 细胞）驻留在人类通常无法接触到的组织中。我们开发了新工具来追踪小鼠和人类中的流感特异性记忆 B 细胞，现在已经识别并表征了小鼠组织中的不同群体，我们认为这些细胞可能有助于持久的疫苗诱导免疫反应。该应用的中心假设是，表达转录因子 T-bet 的流感特异性记忆 B 细胞亚群在肺等组织中长期维持，并通过疫苗接种优先回忆。该提案的具体目标是确定建立肺部驻留表达 T-bet 的记忆 B 细胞所需的疫苗诱导信号，确定疫苗接种和感染是否诱导具有不同功能和寿命的不同记忆 B 细胞群，确定哪些记忆 B 细胞亚群在抗原暴露后优先被召回，并评估在人体组织中发现的表达 T-bet 的记忆 B 细胞的库是否丰富 对个体早年可能遇到的较旧的“历史性”流感抗原的反应。该提案的长期目标是通过开发工具和动物模型系统来填补我们的知识空白，使我们能够系统、全面地研究流感特异性记忆 B 细胞的异质群体，这些细胞持续存在于淋巴和非淋巴组织中，并且是成人疫苗接种的直接目标。我们相信这一贡献意义重大，因为我们期望为复杂且异质的记忆 B 区室提供新的见解，这对于疫苗诱导的流感反应至关重要。