CD4 T Cell Responses to M. Tuberculosis Infection

CD4 T 细胞对结核分枝杆菌感染的反应

• 批准号: 8091340
• 负责人: Michael Stephen Glickman
• 金额: $ 46.53万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8091340
• 关键词: Acute; Address; Adoptive Transfer; Aerosols; Antibodies; Antigens; Applications Grants; CD4 Positive T Lymphocytes; Chronic; Communicable Diseases; Disease; Effectiveness; Epitopes; Flare; Genetic; Genus Mycobacterium; Goals; Growth; Health; Homeostasis; Human; Immune; Immune response; Immune system; Immunity; In Vitro; Infection; Interferons; Kinetics; Laboratories; Lead; Lung; MHC Class II Genes; Measures; Mediating; Memory; Mouse Strains; Mus; Mycobacterium tuberculosis; Organism; Population; Population Heterogeneity; Production; Relative (related person); Role; Signal Transduction; Staging; Sterility; Structure of parenchyma of lung; System; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; TNF gene; Testing; Th1 Cells; Time; Transgenic Mice; Tuberculosis; Vaccines; cytokine; immune clearance; in vivo; long term memory; meetings; memory CD4 T lymphocyte; migration; mycobacterial; novel; novel strategies; pathogen; research study; trafficking

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.

描述（由申请人提供）：CD4 T细胞提供了针对结核分枝杆菌感染的免疫防御。结核分枝杆菌感染的控制也需要TNF，IFN-？，Inos和TLR介导的先天免疫信号。 CD4 T细胞编排了抑制哺乳动物宿主结核分枝杆菌生长的细胞和细胞因子介导的效应器机制。因此，疫苗诱导的长期记忆CD4 T细胞对结核分枝杆菌的启动是重要的，但迄今为止，迄今为止未完全满足目标。提出的实验重点是一个重要的问题：为什么自然感染诱导的CD4 T细胞无法消除宿主的结核分枝杆菌。我们假设自然感染质量混合了效应子和调节性CD4 T细胞，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。为了检验这一假设，我们生成了特异于ESAT-6的T细胞受体转基因小鼠，一种免疫主导的结核分枝杆菌抗原，并在感染过程中跟踪ESAT-6特异性CD4 T细胞。经过转移，TH1分化的ESAT-6特异性CD4 T细胞提供了防止气溶胶感染的保护，从而实现了CD4 T细胞介导的保护性免疫的机械研究。我们的第一个目的是研究结核病感染过程中不同时间的克隆CD4 T细胞激活，扩张和收缩的动力学。这些研究将确定明显的结核分枝杆菌感染的能力是由于特定的T淋巴细胞，特定T细胞的磨损过多或在慢性感染过程中的T细胞效应功能的丧失而产生的。我们的第二个目的是确定保护性免疫需要哪些CD4 T细胞效应子功能。这些实验将确定由TB特异性CD4 T细胞产生IFN-3和/或TNF对于保护是否至关重要，并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。我们的最终目的是确定可以优化体内CD4 T细胞介导的保护的方法。我们将诱导CD4 T细胞迁移到肺实质和气道，优化ESAT-6特异性CD4 T细胞的体内分化，并确定Th17 CD4 T细胞对保护性免疫的贡献。这些研究将为CD4 T细胞对结核分枝杆菌感染的反应提供前所未有的观点，并可能提出新的和实用的方法，以优化针对该病原体的免疫力。公共卫生相关性：针对结核病的疫苗，是面对人类面临的最重要，最困难的传染病之一，仅是部分有效的。我们对免疫防御性结核分枝杆菌的理解，尤其是T淋巴细胞的作用，远非完整。本赠款应用中提出的研究将确定CD4 T细胞用于控制结核病的主要机制。使用在实验室中开发的新型小鼠菌株，我们将发现新的方法来优化结核分枝杆菌的免疫清除率。