CD4 T Cell Responses to M. Tuberculosis Infection

描述（由申请人提供）：CD 4 T细胞提供针对结核分枝杆菌感染的免疫防御。控制M。结核感染也需要TNF，IFN-γ，iNOS和TLR介导的先天免疫信号。CD 4 T细胞协调细胞和亮氨酸介导的抑制M.结核病在哺乳动物宿主中的生长。疫苗诱导的M.因此，结核病是一个重要的目标，但迄今尚未完全实现。拟议的实验集中在一个重要的问题：为什么自然感染诱导的CD 4 T细胞不能消除M。结核病从宿主。我们假设自然感染引发了限制M.但不会导致结核菌生长而产生免疫力。为了验证这一假设，我们产生了对ESAT-6特异的T细胞受体转基因小鼠，ESAT-6是一种免疫显性M。结核抗原，并在感染期间追踪ESAT-6特异性CD 4 T细胞。连续转移的Th 1分化的ESAT-6特异性CD 4 T细胞提供针对气溶胶感染的保护，使得能够进行CD 4 T细胞介导的保护性免疫的机制研究。我们的第一个目的是研究结核病感染过程中克隆性CD 4 T细胞在不同时间的活化、扩增和收缩的动力学。这些研究将确定是否无法明确M。结核病感染是由于在慢性感染期间特异性T淋巴细胞太少、特异性T细胞的损耗或T细胞效应功能的丧失。我们的第二个目标是确定保护性免疫所需的CD 4 T细胞效应子功能。这些实验将确定TB特异性CD 4 T细胞产生的IFN-3和/或TNF是否对保护至关重要，并将确定先天免疫应答对ESAT-6特异性T细胞活化和分化的影响。我们的最终目标是确定优化体内CD 4 T细胞介导的保护的方法。我们将诱导CD 4 T细胞迁移至肺实质和气道，优化ESAT-6特异性CD 4 T细胞的体内分化，并确定Th 17 CD 4 T细胞对保护性免疫的贡献。这些研究将提供CD 4 T细胞对M.结核病感染，并可能提出新的和实用的方法来优化对这种病原体的免疫力。公共卫生相关性：结核病是人类面临的最重要和最困难的传染病之一，其疫苗仅部分有效。我们对结核分枝杆菌免疫防御的理解，特别是T淋巴细胞的作用，还远远没有完成。这项研究将确定CD 4 T细胞用于控制结核病的主要机制。使用我们实验室开发的新型小鼠品系，我们将发现优化M.结核

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.