Tuberculosis and T cell Recognition

 描述(申请人提供)：在小鼠中感染结核分枝杆菌(Mtb)后，强大的T细胞反应在引流层启动，经历大规模扩张，并输送到肺。一旦到达肺部，T细胞就会中止细菌的指数增长，这导致细菌负荷的早期下降，随后细菌数量长期保持稳定。尽管T细胞可以清除大多数细菌，但灭菌从未实现。在最佳条件下，最好的疫苗可将肺部CFU减少20-30倍。因此，最佳的T细胞反应可以清除许多但不是所有的感染细菌--这表明获得更好的感染保护性免疫的一个重要障碍是确定为什么相对较少但具有生物重要性的细菌亚群在其他有效的T细胞介导的免疫面前存活下来。重要的是，虽然免疫成功和失败之间的数量平衡在动物模型和人类之间可能有所不同，但两者都具有免疫控制和逃避的特征。小鼠在开始适应性免疫后清除了大部分细菌，但即使接种了疫苗，也无法对肺部进行消毒。因此，小鼠结核病可能是探索T细胞免疫失败原因的合理模型。为什么细菌亚群可以在T细胞反应中存活下来，而T细胞反应可以清除大部分细菌？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。异质性可能出现在细菌、细菌所在的细胞室或遇到感染细胞的T细胞的水平上。了解T细胞对结核分枝杆菌免疫的平衡成功和失败，对于确定如何更好地设计针对结核分枝杆菌感染的疫苗非常重要。目前尚不清楚是否用不同的抗原组合制造新的亚单位疫苗；应用新的佐剂或不同的结核分枝杆菌减毒株将 解决这个问题。我们推测，设计一种比自然感染或当前疫苗更好的免疫疫苗的第一步是识别导致免疫失败的特征。我们的协调工作将调查关于结核分枝杆菌T细胞免疫的三个基本问题，目的是对疫苗开发产生重大影响。我们的主要假设是，由于T细胞监测和效应器功能的局部失败，细菌即使有强大的T细胞反应也能存活下来。目的1.感染细胞亚群的T细胞识别是否受损？我们假设T细胞识别许多但不是所有感染细胞，并促进结核分枝杆菌的清除。剩下的是一群不能被T细胞识别或激活的感染细胞，并为结核分枝杆菌的持久性提供了一个利基。我们将确定并确定这一利基市场出现的原因。目的2.细菌种群的数量差异是否允许一些结核分枝杆菌细胞逃避T细胞的清除？我们假设，一些受感染的细胞逃脱了识别，因为启动免疫反应的早期抗原的表达在感染后期下调。我们将使用已经被设计成允许变阻器一样控制抗原产生的细菌菌株来确定抗原负荷的定量差异是否会改变T细胞识别或效应器功能。目的3.不同的细胞类型处理和呈现结核分枝杆菌抗原是否不同？T细胞反应反映了由启动DC处理和呈递的抗原。然而，在HIV感染期间，不同类型的细胞(巨噬细胞和DC)中蛋白质的细胞内处理以及抗原呈递是不同的，并且具有不同的激活状态。我们将对结核分枝杆菌感染验证这一假设，假设不同细胞类型呈现的多肽表位的差异允许一些受感染的细胞逃脱T细胞的监视。

 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.