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 我们了解调节保护性免疫的细胞机制；这是当前 求婚。我们在这里表明，疫苗诱导的对结核分枝杆菌(Mtb)的记忆可以限制 细菌的生长，但在模拟自然暴露的条件下，记忆的表达 被推迟了。至关重要的是，这种延迟允许细菌生长。这种生长会导致炎症和 表达记忆反应的环境的改变。基于我们发布的和 我们的初步数据如下：适当的疫苗接种诱导了监测细胞的数量 充斥在肺部的物质。这些细胞通过释放IL-17和随后的趋化因子来应对感染 诱导，招募效应者干扰素-γ，产生能够阻止细菌生长的记忆细胞。至 改进疫苗接种我们需要确定如何产生记忆反应，以迅速对 肺部的结核杆菌感染，我们需要确定一个细胞群体，不仅能够阻止细菌 但能够杀死肺部的细菌。因此，在这个新的应用程序中，我们想要解决两个问题 以我们的工作模式为基础，研究相关问题。第一个问题是确定影响经济增长的因素 肺脏对结核的记忆T细胞反应的诱导和功能(目标一)。第二个是 介导结核分枝杆菌免疫的效应细胞关键功能属性的鉴定 挑战肺部(目标二)。在这份新提交的文件中，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反应细胞。我们还将利用 经验证的细胞转移模型，用于研究T细胞亚群调节免疫保护的能力 结核分枝杆菌肺部挑战。结合项目1，我们将确定调节CD4T细胞的因素 以及确定新的小区子集是否对结核分枝杆菌有效。在项目2中，我们 生成针对结核分枝杆菌的CDS T细胞亚群，并确定这些亚群的防御能力 山地车。在项目3中，我们将确定选择素结合活性识别诱导的细胞亚群的能力 通过疫苗接种和结核分枝杆菌感染，确定PSGL-1活性是否调节 记忆T细胞。 相关性(请参阅说明)： 我们对疫苗诱导的结核病保护性反应是如何发挥作用的知之甚少。如果我们不这样做 知道反应是如何起作用的，很难改进它。通过调查响应的方式 我们已经确定了新的细胞类型，可以作为疫苗接种的靶点。我们将研究这些细胞是如何 这将有可能改善疫苗的保护效果，从而减少 世界上结核病的发病率。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.