Defining mechani1sms of CD8+ T-cell mediated immunity - using an integrated longitudinal model to achieve an elusive goal.

定义 CD8 T 细胞介导的免疫机制 - 使用集成纵向模型来实现难以捉摸的目标。

• 批准号: BB/S017151/1
• 负责人: Tim Connelley
• 金额: $ 67.84万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS017151%2F1
• 关键词: Defining; mechani1sms; CD8+; cell; mediated

Vaccines have been amongst the most successful and cost-effective health intervention strategies implemented and have played a critical role in reducing the incidence of many human and animal diseases. However, for a number of diseases (e.g. HIV, malaria, African Swine Fever) for which CD8+ T-cell mediated immunity is thought to make a substantial contribution to immunity, there are currently no available vaccines that elicit protective CD8+ T-cell responses. Viral-vectored vaccines are the delivery system that has shown most promise, especially in model species. However, in target human or animal species these vaccines, although usually highly immunogenic (induce T-cell responses), have demonstrated only a limited ability to generate protective CD8+ T-cells. The discrepancy between immunogenicity and protection indicates that qualitative, rather than quantitative, parameters of the vaccine-induced T-cell responses are deficient. As yet our understanding of what these parameters are is limited and this 'knowledge-gap' prevents a fully rational approach to design of novel, efficacious vaccine delivery platforms. Theileria parva, a tick-borne protozoan parasite of cattle, causes major economic losses in livestock farming in sub-Saharan Africa of ~$600M/yr. This loss is largely borne by small-holder farmers and can be devastating for some of the most vulnerable people in low/middle income countries. Natural immunity to T. parva is associated with CD8+ T-cell responses, which can be mimicked under experimental conditions using either an 'infection-and-treatment method' (ITM) or autologous T. parva-infected cell line (ACL) immunisation which have been used to study and characterise protective immunity. A major aim of T. parva research has been the development of a subunit vaccine that could be deployed as part of sustainable T. parva control programme. Trials using a variety of viral vectors (canarypox, Ad, MVA) to deliver known T. parva CD8+ T-cell antigens have demonstrated immunogenicity but only limited protection from in vivo challenge. Recent data has implicated defects in Ad/MVA-induced CD4+ T-cell responses as contributing to deficient CD8+ T-cell functionality.Development and trialling of novel viral vectors requires substantial investments of time and resources and is limited by the availability of suitable candidates. Although disappointing, failure of current viral vectors to induce protective CD8+ T-cell responses can be exploited to understand how the induced T-cell responses differ from equivalent but protective T-cell responses.In this project we propose to use a 'longitudinal' model of T. parva immunisation in which the T-cell responses of individuals are intensively analysed following sequential administration of a non-protective (Ad/MVA) and protective (ITM) immunisation to enable the parameters that influence the transition of phenotypes to be analysed and so define the immunological parameters that determine protective efficacy of CD8+ T-cells. By facilitating intra-animal comparisons this model has a number of advantages over conventional cohort studies. The objectives of the project are to define: 1. How does the function and transcriptome of non-protective CD8+ T-cells induced by Ad/MVA heterologous prime-boost differ from protective T. parva-specific CD8+ T-cells? 2. How does the function and transcriptome of CD4+ T-cells induced by Ad/MVA heterologous prime-boost differ from those associated with protection from T. parva infection? 3. How dependent on CD4+ T-cells is the functional competency of CD8+ T-cells? This information will provide the data to understand the fundamental immunological mechanisms that dictate CD8+ T-cell vaccine success or failure and can be used to inform the design/engineering of improved novel vaccine vectors for T. parva and other human and veterinary pathogens.

疫苗是实施的最成功和最具成本效益的卫生干预战略之一，在减少许多人类和动物疾病的发病率方面发挥了关键作用。然而，对于一些疾病(如艾滋病毒、疟疾、非洲猪瘟)，CD8+T细胞介导的免疫被认为对免疫做出了重大贡献，目前还没有可用的疫苗来激发保护性CD8+T细胞反应。病毒载体疫苗是最有希望的递送系统，特别是在模式物种中。然而，在目标人类或动物物种中，这些疫苗虽然通常具有高度的免疫原性(诱导T细胞反应)，但仅显示出产生保护性CD8+T细胞的有限能力。免疫原性和保护性之间的差异表明，疫苗诱导的T细胞反应的定性参数而不是定量参数是不足的。到目前为止，我们对这些参数的了解是有限的，这种“知识鸿沟”阻碍了设计新的、有效的疫苗交付平台的完全理性的方法。微小泰勒氏菌是一种由壁虱传播的牛的原生动物寄生虫，每年给撒哈拉以南非洲的畜牧业造成约6亿美元的重大经济损失。这种损失主要由小农承担，对低收入/中等收入国家的一些最脆弱的人来说可能是毁灭性的。对微小毛滴虫的自然免疫与CD8+T细胞反应有关，在实验条件下，可以使用感染和治疗方法(ITM)或自体微小毛滴虫感染细胞系(ACL)免疫来模拟这一反应，这已被用于研究和表征保护性免疫。微小毛滴虫研究的一个主要目标是开发一种亚单位疫苗，该疫苗可作为可持续的细小毛滴虫控制计划的一部分部署。使用各种病毒载体(金丝雀痘、Ad、MVA)传递已知的微小弓形虫CD8+T细胞抗原的试验表明具有免疫原性，但对体内攻击的保护有限。最近的数据表明，Ad/MVA诱导的CD4+T细胞应答的缺陷是导致CD8+T细胞功能缺陷的原因之一。开发和试验新型病毒载体需要大量的时间和资源投入，并受到合适候选者的限制。尽管令人失望，但目前的病毒载体未能诱导保护性CD8+T细胞反应，可以用来理解诱导的T细胞反应与同等但保护性T细胞反应的不同。在这个项目中，我们建议使用T.parva免疫的“纵向”模型，在该模型中，在连续接种非保护性(Ad/MVA)和保护性(ITM)免疫后，对个体的T细胞反应进行密集分析，以便能够分析影响表型转换的参数，从而定义决定CD8+T细胞保护性有效性的免疫学参数。通过促进动物内比较，该模型比传统的队列研究有许多优势。该项目的目标是确定：1.在Ad/MVA异源Prime-Boost诱导下，非保护性CD8+T细胞的功能和转录组与保护性T细胞有何不同？2.Ad/MVA异源Prime-Boost诱导的CD4+T细胞的功能和转录组与弓形虫感染相关的有何不同？3.CD8+T细胞的功能能力在多大程度上依赖于CD4+T细胞？这些信息将为理解决定CD8+T细胞疫苗成败的基本免疫学机制提供数据，并可用于为针对微小旋毛虫和其他人类和兽医病原体的改进的新型疫苗载体的设计/工程提供信息。