T cell memory to TB in the lung

结核病是一个严重的公共卫生问题，合理开发有效的疫苗需要 我们了解介导保护性免疫的细胞机制;这是目前的重点 提议我们在这里表明，疫苗诱导的记忆结核分枝杆菌（Mtb）可以限制 但在模拟自然暴露的条件下，记忆的表达 已经推迟了。至关重要的是，这种延迟允许细菌生长。这种生长导致炎症， 改变记忆反应的表达环境。根据我们发布的和 初步数据，我们提出以下建议：适当的疫苗接种诱导一个群体的监视细胞 分布在肺部这些细胞通过启动IL-17释放和随后的趋化因子来响应感染。 诱导，其募集能够停止细菌生长的产生效应IFN-γ的记忆细胞。到 我们需要确定如何产生一种记忆反应， 我们需要鉴定出一群不仅能阻止细菌感染， 生长，但能够杀死肺部的细菌。因此，在这个新的应用程序中，我们要解决两个问题 相关问题使用我们的工作模型作为基础。第一，确定了影响经济增长的因素， 肺中记忆T细胞对TB应答的诱导和功能（目的一）。二是 鉴定能够介导对Mtb的免疫的效应细胞的关键功能属性 肺部挑战（目标二）。在这项新的提交中，我们将利用结核分枝杆菌特异性TcRTg小鼠，细胞因子- 报告小鼠和四聚体试剂来分析抗原特异性应答细胞。我们还将利用 经证实的细胞转移模型，以研究确定的T细胞亚群介导抗 肺结核挑战结合项目1，我们将确定调节CD 4 T细胞的因素， 亚群以及确定新的细胞亚群是否对Mtb有活性。项目2我们 产生对Mtb特异性的CD 8 T细胞亚群，并确定这些亚群保护免受Mtb感染的能力。 Mtb.在项目3中，我们将确定选择素结合活性的能力，以识别诱导的细胞亚群。 通过疫苗接种和Mtb感染，并确定PSGL-1活性是否调节 记忆T细胞 相关性（参见说明）： 我们对疫苗诱导的结核病保护性反应如何起作用知之甚少。如果我们不 知道响应是如何工作的，很难改进它。通过调查响应的工作方式， 我们已经鉴定了可以通过疫苗接种靶向的新细胞类型。我们将研究这些细胞是如何 这将有可能提高疫苗的保护作用，从而减少 结核病在全世界的发病率。这将对全球公共卫生产生重大影响。

Tuberculosis (TB) is a serious public health issue and rational development of effective vaccines requires that we understand the cellular mechanisms mediating protective immunity; this is the focus of the current proposal. We show here that vaccine-induced memory to Mycobacterium tuberculosis (Mtb) can limit bacterial growth but that under conditions that mimic a natural exposure, the expression of memory Is delayed. Crucially, this delay allows bacterial growth to occur. This growth results in inflammation and the alteration of the environment in which the memory response is expressed. Based on our published and preliminary data we propose the following: Appropriate vaccination induces a population of surveillance cells that populate the lung. These cells respond to infection by initiating IL-17 release and subsequent chemokine induction, which recruits effector IFN-y producing memory cells capable of stopping bacterial growth. To improve vaccination we need to determine how to generate a memory response that can respond rapidly to Mtb infection in the lung and we need to identify a population of cells capable of not only stopping bacterial growth but capable of killing bacteria in the lung. In this new application therefore we want to address two related issues using our working model as a base. The first is the determination of the factors regulating the induction and function of the memory T cell response to TB in the lung (Aim One). The second is the identification of crucial functional attributes of the effector cells capable of mediating immunity to Mtb challenge in the lung (Aim Two). In this new submission we will utilize Mtb-specific TcRTg mice, cytokine- reporter mice and tetramer reagents to analyze antigen-specific responding cells. We will also utilize a proven cell transfer model to investigate the ability of defined subsets of T cell to mediate protection against pulmonary challenge with Mtb. In conjunction with Project 1 we will identify the factors regulating CD4 T cell subsets as well as determining whether novel subsets of cells are active against Mtb. With Project 2 we generate CDS T cell subsets specific for Mtb and determine the ability of these subsets to protect against Mtb. With Project 3 we will determine the ability of selectin-binding activity to identify subsets of cells induced by vaccination and Mtb Infection and determine whether PSGL-1 activity regulates the protective ability of memory T cells. RELEVANCE (See instructions): We know too little about how the vaccine-induced protective response to tuberculosis works. If we do not know how the response works it is difficult to improve upon it. By investigating the way the response works we have identified new cell types that can be targeted by vaccination. We will investigate how these cells are regulated and this will have the potential to improve the protective effect of vaccines and thereby reduce the incidence of tuberculosis in the world. This will have a significant impact in worldwide public health.