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（由适用提供）：在小鼠病毒结核病（MTB）感染之后，在排水LN中引发了强大的T细胞反应，经历大量扩张和肺部的流量。到达肺后，T细胞中止了指数级细菌的生长，这会导致细菌燃烧的早期下降，然后长期稳定细菌数量。尽管T细胞介导了大多数细菌的清除，但从未实现灭菌。在最佳条件下，最好的疫苗可减少肺CFU的20-30倍。这是最佳的T细胞反应可以清除许多但并非所有被感染的细菌，这是实现更好的保护性免疫疗法感染的重要障碍，这是为了确定为什么相对较小但具有生物学上重要的细菌亚群在否则有效的T细胞介导的免疫疗法的情况下生存。重要的是，尽管成功免疫和失败之间的定量平衡在动物模型和人之间可能有所不同，但两者都具有免疫控制和逃生的特征。小鼠在自适应免疫发作后清除大多数细菌，但即使接种疫苗也无法刻板印象。那就是鼠结核病可能是探索为什么T细胞免疫型失败的合理模型。为什么面对可以清除大多数细菌群体的T细胞反应，细菌的亚群可以生存？与被清除的细菌相比，在鲁棒的适应性免疫史上，在稳健的适应性免疫（们面对强大的适应性免疫史前）中似乎有些不同。异质性可能是在细菌的水平，其居住的细胞室或遇到感染细胞的T细胞上产生的。了解T细胞免疫（对MTB）的平衡成功和失败对于确定如何更好地针对MTB感染设计疫苗很重要。目前尚不清楚是否制造具有不同抗原组合的新亚基疫苗。新调整或不同的MTB菌株的应用将 解决这个问题。我们假设，设计一种疫苗的第一步，该疫苗比自然感染或当前疫苗引起的疫苗更好，该疫苗比自然感染或当前疫苗引起的疫苗更好。我们协调的工作将调查有关T细胞免疫对MTB的三个基本问题，目的是对疫苗开发产生重大影响。我们的总体假设是，由于T细胞监测和效应子功能的局部衰竭，细菌仍然存在，尽管T细胞反应有强大。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细胞识别许多但并非全部感染的细胞，并促进MTB清除率。剩下的是一个无法被T细胞识别或激活的感染细胞群，并为MTB持久性提供了一个利基。我们将确定并确定为什么出现这种利基市场。目标2。细菌群中的定量差异是否会使某些MTB细胞逃脱T细胞清除率？我们假设某些感染细胞逃脱了识别，因为在感染的后期，启动免疫激素的早期抗原的表达被下调。我们将使用已设计的细菌菌株来允许对抗原产生的类似抗原的控制，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。 AIM 3。进行不同的细胞类型过程并以不同的方式呈现MTB抗原？ T细胞反应反映了启动直流处理和提出的抗原。但是，在HIV感染期间，蛋白质的细胞内加工及其抗原表现在不同的细胞类型（巨噬细胞与DC）和不同的激活状态下有所不同。我们将对MTB感染进行检验，并假定不同细胞类型提出的胡椒表位的差异使一些受感染的细胞逃脱了T细胞监测。