CD4 T Cell Responses to M. Tuberculosis Infection

描述(申请人提供)：CD4T细胞提供对结核分枝杆菌感染的免疫防御。控制结核分枝杆菌感染还需要肿瘤坏死因子、干扰素、诱导型一氧化氮合酶和TLR介导的天然免疫信号。CD4T细胞协调细胞和细胞因子介导的效应机制，抑制哺乳动物宿主中结核分枝杆菌的生长。因此，疫苗诱导结核分枝杆菌特异性长期记忆CD4T细胞的启动是一个重要的目标，但到目前为止，还没有完全实现。拟议的实验集中在一个重要的问题上：为什么自然感染诱导的CD4T细胞无法从宿主中消除结核分枝杆菌。我们假设，自然感染启动了效应和调节性CD4T细胞的混合群体，这些细胞限制了结核分枝杆菌的生长，但不会导致无菌免疫。为了验证这一假设，我们培育了针对ESAT-6的T细胞受体转基因小鼠，ESAT-6是一种免疫优势的结核分枝杆菌抗原，并在感染期间跟踪了ESAT-6特异性的CD4T细胞。通过过继转移，Th1分化的ESAT-6特异性CD4T细胞提供了对气雾剂感染的保护，使CD4T细胞介导的保护性免疫的机制研究成为可能。我们的第一个目的是研究在结核病感染过程中克隆性CD4T细胞在不同时间的激活、扩增和收缩的动力学。这些研究将确定是否由于特定T淋巴细胞太少、特定T细胞磨损或慢性感染期间T细胞效应器功能丧失而导致无法清除结核分枝杆菌感染。我们的第二个目标是确定保护性免疫需要哪些CD4T细胞效应器功能。这些实验将确定结核特异性CD4T细胞产生的干扰素-3和/或肿瘤坏死因子是否对保护至关重要，并将确定先天免疫反应对ESAT-6特异性T细胞激活和分化的影响。我们的最终目标是确定优化体内CD4T细胞介导的保护的方法。我们将诱导CD4T细胞向肺实质和呼吸道迁移，优化ESAT-6特异性CD4T细胞的体内分化，并确定Th17CD4T细胞在保护性免疫中的作用。这些研究将提供关于CD4T细胞对结核分枝杆菌感染反应的前所未有的看法，并可能提出新的实用方法来优化对这种病原体的免疫。公共卫生相关性：结核病疫苗是人类面临的最重要和最困难的传染病之一，但只有部分有效。我们对结核分枝杆菌的免疫防御，特别是T淋巴细胞的作用的了解还远远不完整。这项拨款申请中提出的研究将确定CD4T细胞用于控制结核病的主要机制。使用我们实验室开发的一种新的小鼠品系，我们将发现优化结核分枝杆菌免疫清除的新方法。

DESCRIPTION (provided by applicant): CD4 T cells provide immune defense against Mycobacterium tuberculosis infection. Control of M. tuberculosis infection also requires TNF, IFN-?, iNOS and TLR-mediated innate immune signals. CD4 T cells orchestrate cellular and cytokine-mediated effector mechanisms that inhibit M. tuberculosis growth in the mammalian host. Vaccine induced priming of long-term memory CD4 T cells specific for M. tuberculosis, therefore, is an important but, to date, incompletely met goal. The proposed experiments focus on an important question: Why are CD4 T cells induced by natural infection unable to eliminate M. tuberculosis from the host. We hypothesize that natural infection primes mixed populations of effector and regulatory CD4 T cells that restrict M. tuberculosis growth but do not lead to sterile immunity. To test this hypothesis, we generated T cell receptor transgenic mice specific for ESAT-6, an immunodominant M. tuberculosis antigen, and tracked ESAT-6 specific CD4 T cells during infection. Adoptively transferred, Th1 differentiated ESAT-6 specific CD4 T cells provide protection against aerosol infection, enabling mechanistic studies of CD4 T cell mediated protective immunity. Our first aim is to investigate the kinetics of clonal CD4 T cell activation, expansion and contraction at different times during the course of TB infection. These studies will determine whether the inability of clear M. tuberculosis infection results from too few specific T lymphocytes, attrition of specific T cells or loss of T cell effector functions during chronic infection. Our second aim is to determine which CD4 T cell effector functions are required for protective immunity. These experiments will determine whether IFN-3 and/or TNF production by TB-specific CD4 T cells are essential for protection, and will determine the impact of innate immune responses on activation and differentiation of ESAT-6-specific T cells. Our final aim is to identify approaches that optimize in vivo, CD4 T cell-mediated protection. We will induce migration of CD4 T cells to lung parenchyma and airways, optimize in vivo differentiation of ESAT-6 specific CD4 T cells and determine the contribution of Th17 CD4 T cells to protective immunity. These studies will provide unprecedented views of CD4 T cell responses to M. tuberculosis infection and will likely suggest new and practical approaches to optimize immunity against this pathogen. PUBLIC HEALTH RELEVANCE: Vaccines against Tuberculosis, one of the most important and difficult infectious diseases confronting mankind, are only partially effective. Our understanding of immune defense against Mycobacterium tuberculosis, in particular the role of T lymphocytes, is far from complete. The studies proposed in this grant application will determine the major mechanisms that CD4 T cells use to control Tuberculosis. Using a novel mouse strain that was developed in our laboratory, we will discover new approaches to optimize immune clearance of M. tuberculosis.