T cell memory to TB in the lung

T细胞对肺部结核病的记忆

• 批准号: 8379745
• 负责人: ANDREA M COOPER
• 金额: $ 46.53万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8379745
• 关键词: Address; Adjuvant; Aerosols; Antigens; Bacteria; Binding; Boxing; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Cells; Data; Development; Effector Cell; Environment; Generations; Goals; Growth; Immunity; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Instruction; Interferons; Interleukin-10; Interleukin-12; Interleukin-17; Interleukin-6; Location; Lung; Lymphoid; Mediating; Memory; Modeling; Molecular; Mus; Mycobacterium tuberculosis; P-selectin ligand protein; Peptides; Performance; Population; Population Surveillance; Production; Public Health; Publishing; Reagent; Recruitment Activity; Regulation; Regulatory Pathway; Regulatory T-Lymphocyte; Reporter; Selectins; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tuberculosis; Vaccinated; Vaccination; Vaccines; Work; base; cell type; chemokine; cytokine; glycosylation; improved; interleukin-12 subunit p40; interleukin-23; killings; lymph nodes; macrophage; memory CD4 T lymphocyte; migration; novel; pathogen; protective effect; receptor; research study; response; tool; vaccine efficacy; vaccine-induced immunity

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.

结核病（TB）是一个严重的公共卫生问题，有效疫苗的合理发展需要 我们了解介导保护性免疫的细胞机制；这是当前的重点 提议。我们在这里表明，疫苗引起的记忆到结核分枝杆菌（MTB）可能会限制 细菌生长，但在模仿自然暴露的条件下，记忆的表达 延迟。至关重要的是，这种延迟允许细菌生长发生。这种增长导致炎症和 表达内存响应的环境的改变。根据我们出版的 初步数据我们提出以下内容：适当的疫苗接种诱导监视细胞的群体 填充肺部。这些细胞通过启动IL-17释放和随后的趋化因子来应对感染 诱导，募集效应子IFN产生能够停止细菌生长的记忆细胞。到 改善疫苗接种我们需要确定如何产生可以迅速响应的内存响应 肺中的MTB感染，我们需要识别能够停止细菌的细胞群 生长，但能够杀死肺部细菌。因此，在这个新应用中，我们要解决两个 使用我们的工作模型作为基础的相关问题。首先是确定调节的因素 记忆T细胞对肺中TB的诱导和功能（AIM ONE）。第二个是 鉴定能够介导对MTB免疫力的效应细胞的关键功能属性 肺中的挑战（目标两个）。在此新提交中，我们将使用MTB特异性的TCRTG小鼠，细胞因子 - 记者小鼠和四聚体试剂分析抗原特异性反应细胞。我们还将利用 经过验证的细胞转移模型，研究了定义的T细胞子集介导保护的能力 MTB的肺挑战。结合项目1，我们将确定调节CD4 T细胞的因素 子集以及确定新颖的细胞子集是否对MTB活性。与项目2我们 生成针对MTB的CDS T细胞子集，并确定这些子集预防的能力 MTB。使用项目3，我们将确定选择素结合活性识别细胞诱导的子集的能力 通过疫苗接种和MTB感染，并确定PSGL-1活性是否调节了保护能力 记忆T细胞。 相关性（请参阅说明）： 我们对疫苗诱导的对结核病的保护性反应的作用知之甚少。如果我们不 知道响应是如何工作的，很难改善它。通过调查响应的工作方式 我们已经确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的 受监管，这将有可能改善疫苗的保护作用，从而减少 世界结核病的发生率。这将对全球公共卫生产生重大影响。