Tuberculosis and T cell Recognition

结核病和 T 细胞识别

• 批准号: 9221970
• 负责人: SAMUEL M BEHAR
• 金额: $ 69.83万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9221970
• 关键词: Adjuvant; Affect; Animal Model; Anti-Bacterial Agents; Antigen Presentation; Antigens; Attenuated; Bacteria; Bacterial Proteins; Binding Proteins; Biological; Cells; Cellular Immunity; Defect; Disease; Engineering; Epitopes; Equilibrium; Failure; Goals; Growth; HIV Infections; Heterogeneity; Human; Immune; Immune response; Immunity; Impairment; Infection; Lead; Lung; Mediating; Modeling; Mus; Mutate; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Myeloid Cells; Organism; Pattern; Peptides; Population; Problem Solving; Process; Production; Proteins; Pulmonary Tuberculosis; Regulation; Research; Research Proposals; Signal Transduction; Sterilization; Subunit Vaccines; T cell response; T-Lymphocyte; Testing; Tuberculosis; Vaccinated; Vaccines; Variant; Virulent; Work; adaptive immunity; antigen processing; cell type; design; functional plasticity; global health; immune clearance; improved; killings; macrophage; multidisciplinary; mycobacterial; novel vaccines; pathogen; pressure; protein degradation; protein expression; public health relevance; success; targeted treatment; tool; tuberculosis immunity; vaccine development

 DESCRIPTION (provided by applicant): Following virulent Mycobacterium tuberculosis (Mtb) infection in mice, a robust T cell response is primed in the draining LN, undergoes massive expansion, and traffics to the lung. Upon reaching the lung, T cells abort exponential bacterial growth, which leads to an early decline in bacterial burden followed by stabilization of the bacterial numbers long term. Despite T cell mediated clearance of most bacteria, sterilization is never achieved. Under optimal conditions, the best vaccines provide a 20-30-fold reduction in lung CFU. Thus, an optimal T cell response clears many but not all of the infecting bacteria-suggesting an important hurdle to achieving better protective immunity to infection is to determine why a relatively small, but biologically important subpopulation of bacteria survive in the face of otherwise effective T cell mediated immunity. Importantly, while the quantitative balance between successful immunity and failure may vary between animal models and people, both have features of both immune control and escape. Mice clear most bacteria after the onset of adaptive immunity but are unable to sterilize the lung, even if vaccinated. Thus, murine TB may be a reasonable model to explore why T cell immunity fails. Why might a subpopulation of bacteria survive in the face of a T cell response that can clear most of the bacterial population? There appears to be something different about the infectious course of the bacteria that survive in the face of robust adaptive immunity as compared to the ones that are cleared. Heterogeneity may arise at the level of the bacterium, the cellular compartment in which it resides, or the T cells that encounter infected cells. Understanding the balanced success and failure of T cell immunity to Mtb is important for determining how to better design a vaccine against Mtb infection. It is currently not clear whether making a new subunit vaccine with a different combination of antigens; application of a new adjuvant or a different attenuated strain of Mtb will solve this problem. We postulate that the first step towards designing a vaccine that elicits immunity that is better than that elicited by natural infection or current vaccines is identifying he features that drive immune failure. Our coordinated effort will investigate three fundamental questions about T cell immunity to Mtb, with the goal of having a major impact on vaccine development. Our overarching hypothesis is that bacteria survive despite a robust T cell response because of a local failure in T cell surveillance and effector function. Aim 1. Is T cell recognition of a subpopulation of infected cells impaired? We hypothesize that T cells recognize many but not all infected cells, and promote Mtb clearance. What remains is a population of infected cells that cannot be recognized or activated by T cells, and provides a niche for Mtb persistence. We will identify and determine why this niche emerges. Aim 2. Do quantitative differences in the bacterial population allow some Mtb cells to escape T cell clearance? We hypothesize that some infected cells escape recognition because expression of the early antigens that primed the immune response are downregulated later in infection. We will use bacterial strains that have been engineered to allow rheostat-like control of antigen production to determine whether quantitative differences in antigen load alter T cell recognition or effector function. Aim 3. Do distinct cell types process and present Mtb antigens differently? The T cell response reflects the antigens processed and presented by the priming DC. However, during HIV infection, intracellular processing of proteins and thus antigen presentation varies in different cell types (macrophages vs. DC) and with different activation states. We will test this hypothesis for Mtb infection, postulating that differences in the peptide epitopes presented by different cell types allow some infected cells to escape T cell surveillance.

 描述（由申请人提供）：小鼠中的毒性结核分枝杆菌（Mtb）感染后，在引流LN中引发了强烈的T细胞应答，经历了大量扩增，并运输至肺。在到达肺后，T细胞中止细菌的指数生长，这导致细菌负荷的早期下降，随后细菌数量长期稳定。尽管T细胞介导的大多数细菌的清除，灭菌从未实现。在最佳条件下，最好的疫苗可使肺CFU减少20-30倍。因此，最佳的T细胞应答清除了许多但不是所有的感染细菌，这表明实现对感染的更好的保护性免疫的重要障碍是确定为什么相对较小但生物学上重要的细菌亚群在面对其他有效的T细胞介导的免疫时存活。重要的是，虽然成功免疫和失败免疫之间的定量平衡可能在动物模型和人类之间存在差异，但两者都具有免疫控制和逃避的特征。小鼠在获得性免疫开始后清除了大多数细菌，但即使接种了疫苗，也无法对肺部进行消毒。因此，小鼠TB可能是探索T细胞免疫失败原因的合理模型。为什么一个细菌亚群在面对可以清除大部分细菌的T细胞反应时存活下来？与被清除的细菌相比，在强大的适应性免疫面前存活的细菌的感染过程似乎有所不同。异源性可以在细菌、其所在的细胞区室或遇到受感染细胞的T细胞水平上产生。了解T细胞对Mtb免疫的平衡成功和失败对于确定如何更好地设计针对Mtb感染的疫苗是重要的。目前尚不清楚是否用不同的抗原组合制备新的亚单位疫苗;应用新的佐剂或不同的Mtb减毒株将 解决这个问题.我们假设，设计一种疫苗的第一步是确定驱动免疫失败的特征，这种疫苗能激发比自然感染或现有疫苗更好的免疫力。我们的协调努力将调查关于T细胞对结核分枝杆菌免疫的三个基本问题，目标是对疫苗开发产生重大影响。我们的总体假设是，尽管有强大的T细胞应答，但由于T细胞监视和效应子功能的局部失败，细菌仍然存活。目标1. T细胞对感染细胞亚群的识别是否受损？我们假设T细胞识别许多但不是所有感染的细胞，并促进Mtb清除。剩下的是一群不能被T细胞识别或激活的感染细胞，并为Mtb的持续存在提供了一个利基。我们将确定和确定为什么这个利基出现。目标2.细菌群体的数量差异是否允许一些Mtb细胞逃避T细胞清除？我们假设，一些感染的细胞逃避识别，因为表达的早期抗原，引发免疫反应，在感染后期下调。我们将使用经过工程改造的细菌菌株，允许变阻器样控制抗原产生，以确定抗原负荷的定量差异是否会改变T细胞识别或效应子功能。目标3.不同的细胞类型是否以不同的方式处理和呈递Mtb抗原？T细胞应答反映了由致敏DC加工和呈递的抗原。然而，在HIV感染期间，蛋白质的细胞内加工以及因此抗原呈递在不同的细胞类型（巨噬细胞与DC）中变化并且具有不同的活化状态。我们将检验结核杆菌感染的这一假设，假设不同细胞类型呈现的肽表位差异允许一些受感染的细胞逃脱T细胞的监视。