Cytotoxic T Cell Responses to Virus Infection

细胞毒性 T 细胞对病毒感染的反应

• 批准号: 8524204
• 负责人: J. Lindsay Whitton
• 金额: $ 47.38万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8524204
• 关键词: Affect; Antiviral Agents; Biological; CD8B1 gene; Cell Communication; Cell Cycle; Cells; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Down-Regulation; Event; Gene Expression; Generations; Genes; Grant; Hour; Immune; In Vitro; Individual; Infection; Interferons; Interleukin-2; Measurable; Measures; Memory; Molecular; Mus; Pathway interactions; Peripheral; Phenotype; Play; Proteins; Proteomics; Regulation; Research Personnel; Role; Signal Transduction; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Testing; Time; Transgenic Mice; Vaccination; Viral; Viral Antigens; Virus; Virus Diseases; Virus Replication; cytokine; in vivo; interest; mRNA Expression; pathogen; response; secondary infection; vaccine efficacy

DESCRIPTION (provided by applicant): CD8+ memory T cells are one of the cornerstones of successful vaccination, and much is known about their generation, i.e. the pathways that determine na¿ve CD8+ T cell activation, expansion & contraction, and the factors that affect the establishment of CD8+ memory T cell subsets. In contrast, we know relatively little about CD8+ memory T cell recall responses, upon which vaccine efficacy relies. Memory cells deal with individual virus-infected cells in vivo and, to do so effectively, they must respond to secondary infection (i.e., begin their recall response) by imposing their effector functions upon an infected cell before virus progeny has been released; for many virus infections, this means that - if they are to be maximally protective - memory T cells must act within hours of infection. Hence, my lab recently has begun to investigate the very early (d24 hours p.i.) recall responses of CD8+ memory T cells; and, so far as is possible, we measure the responses in vivo. Unpublished data (presented herein) show that: (i) CD8+ memory T cells initiate effector responses to virus infection in vivo within 3-6 hours (long before a single round of virus replication has been completed); and (ii) very surprisingly, in vivo cytokine synthesis (IFN¿, TNF & IL-2) is largely terminated soon thereafter (by 24 hours p.i.). This termination of effector function occurs despite the presence of immunostimulatory viral antigen, suggesting that there is active down-regulation of effector function by CD8+ memory T cells that have responded to infection. These events occur before the memory T cells have multiplied. These early recall responses, and the molecular mechanisms that control them, will be explored in four Specific Aims. 1. To investigate the in vivo regulation of CD8+ memory T cell early recall responses. Our observations regarding the rapid on/off expression of effector functions by CD8+ memory T cells will be expanded. 2. To identify and manipulate the molecular pathway(s) underpinning the early recall response of CD8+ memory T cells. The molecular mechanisms regulating the initiation, and the termination, of effector function(s) will be identified using several approaches. 3. To evaluate the role of dendritic cells in regulating these very early memory T cell responses. The majority of studies of DC / T cell interactions have (understandably) focused on priming of na¿ve T cells. Here, we shall evaluate the role of DCs in the rapid in vivo responses of CD8+ memory T cells. 4. To generate and test a mouse line that would allow us, for the first time, to evaluate the importance of various proteins in regulating the recall responses of CD8+ memory T cells. We shall generate a transgenic mouse line which will allow the investigator to deletion a gene from CD8+ T cells at the time of his/her choosing. An infected mouse would mount a completely normal primary T cell response, and would establish a normal memory cell pool; only then would we delete the gene of interest.

描述（由应用程序提供）：CD8+记忆T细胞是成功疫苗接种的基石之一，并且对它们的产生知之甚少，即确定NA¿VECD8+ T细胞激活，扩张和收缩的途径，以及影响CD8+ Memory T细胞子集建立的因素。相反，我们对CD8+记忆T细胞回忆反应的了解相对较少，疫苗有效性依赖于此。记忆细胞在体内处理单个病毒感染的细胞，为了有效地，他们必须通过将其效应子功能强加于受感染的功能来应对继发感染（即开始召回反应） 病毒进展之前的细胞已释放；对于许多病毒感染，这意味着 - 如果要受到最大保护，则记忆T细胞必须在感染后数小时内作用。因此，我的实验室最近开始研究CD8+记忆T细胞的早期（D24小时）回忆的反应。而且，尽可能地测量体内反应。未发表的数据（本文介绍）表明：（i）CD8+记忆T细胞在3-6小时内启动对体内病毒感染的效应子反应（早在完成一轮病毒复制之前）； （ii）非常令人惊讶的是，体内细胞因子合成（IFN¿，TNF＆il-2）之后很快被终止（P.I. 24小时）。这种效应功能的终止是绝望的 免疫刺激病毒抗原的存在，表明CD8+记忆T细胞对感染有反应的效应子功能有效下调。这些事件发生在记忆T细胞成倍增加之前。这些早期的召回反应以及控制它们的分子机制将在四个特定目标中探索。 1。研究CD8+记忆T细胞的体内调节早期回忆反应。我们的观察结果考虑了CD8+记忆T细胞的效应函数快速/OFF表达的观察结果。 2。识别和操纵分子途径（S）基础CD8+记忆T细胞的早期召回响应。控制主动性的分子机制和效应函数的终止，将使用多种方法鉴定。 3。评估树突状细胞在确定这些早期记忆T细胞反应中的作用。 DC / T细胞相互作用的大多数研究（可以理解）集中在Na ve T细胞的启动上。在这里，我们将评估DC在CD8+记忆T细胞快速体内反应中的作用。 4。生成和测试一条小鼠线，这将使我们首次评估各种蛋白质在确定CD8+记忆T细胞的回忆响应中的重要性。我们将生成一个转基因小鼠系，该系列将使研究人员在选择时从CD8+ T细胞中删除基因。感染的小鼠将安装完全正常的原发性T细胞响应，并建立正常的存储单元池。只有这样，我们才会删除感兴趣的基因。