Antigen-specific CD8+ T cells and protective immunity to tuberculosis

抗原特异性 CD8 T 细胞和结核病保护性免疫

基本信息

批准号：
7737886
负责人：
SAMUEL M BEHAR
金额：
$ 37.72万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-12-15 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7737886
关键词：
AIDS/HIV problem Abbreviations Acquired Immunodeficiency Syndrome Address Adenoviruses Adult Affect Antigen-Presenting Cells Antigens Area Attention Attenuated Bone Marrow Bronchoalveolar Lavage CD8B1 gene Cell-Mediated Cytolysis Cells Cellular Immunity Cessation of life Chronic Colony-forming units Communicable Diseases Cytolysis Cytoplasmic Granules Dendritic Cells Disease Drug resistance in tuberculosis Enzyme-Linked Immunosorbent Assay Epidemic Epitopes Exocytosis Genes Genetic Models Genome Genus Mycobacterium Green Fluorescent Proteins Host Defense Host resistance Human Immune response Immunity Immunofluorescence Immunologic Individual Infection Infection Control Interferons Interleukins International Intramuscular Intravenous Knock-out Laboratories Life Lipopolysaccharides Lung MHC Class I Genes Major Histocompatibility Complex Mediating Molecular Monoclonal Antibodies Mononuclear Multi-Drug Resistance Mus Mycobacterium tuberculosis Natural Killer Cells Pathway interactions Process Proteins Public Health Pulmonary Tuberculosis Recombinants Research Research Personnel Role Scourge Serum T cell response T memory cell T-Cell Development T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Toll-like receptors Tuberculosis Tumor Necrosis Factor-alpha Tumor Necrosis Factors Vaccinated Vaccination Vaccine Design Vaccines Vaccinia virus Virulence Virulence Factors base cell killing combat cytotoxic design fetal in vivo interest intraperitoneal killings lymph nodes macrophage mycobacterial pathogen prevent programs recombinant virus recombinase resistant strain respiratory response tuberculosis immunity vaccine development vaccine-induced immunity

项目摘要

The public health problems posed by tuberculosis have grown more serious as a consequence of the global AIDS epidemic and the emergence of multidrug resistant strains of M. tuberculosis. To combat this worldwide scourge, vaccine development for tuberculosis is an international priority. Cellular immunity to M. tuberculosis is critical in controlling the infection and both CD4"and CD8+ T cells are important. Because CD8+ T cells are required for immunity to tuberculosis, there is great interest in vaccine strategies that elicit M. tuberculosis-specific CD8+ T cells. However, evaluating the role of CD8+ T cells in host resistance and vaccine-induced immunity has been hampered because few class I MHC-presented mycobacterial antigens have been identified. Thus, even basic questions concerning the function of CD8+ T cells during M. tuberculosis infection remain unanswered. We have identified an epitope of the CFP10 protein that is recognized by up to 30% of the CD8+ T cells in the lungs of mice following respiratory M. tuberculosis infection. The CFP10 gene is located within the RD1 region of the mycobacterial genome, which is required for the virulence of M. tuberculosis, and it is likely that CFP10 is mycobacterial virulence factor. Furthermore, it is a major target of the immune response and most people infected with M. tuberculosis have evidence of B and T cell immunity to the CFP10 antigen. We propose to investigate the role of CFPiO- specific CD8+ T cells in immunity to M. tuberculosis. In Aim 1, the molecular basis for in vivo CD8+ T cell- mediated cytotoxicity will be established. These results will determine whether CTL primed during M. tuberculosis infection kill target cells by cytotoxic granule exocytosis, the CD95/95L pathway, or by another mechanism. We will also address whether infected macrophages are killed in vivo. Aim 2 addresses whether CFP10-specific CD8+ T cells elicited by vaccination can protect mice against respiratory challenge with M. tuberculosis. CFP10-vaccinated mice will be challenged with M. tuberculosis and how CFP10- specific CD8+ T cells respond following challenge and whether these T cells contribute to host resistance will be determined. Aim 3 will specifically determine whether cytotoxic activity or other IFNy-independent functions are required for the protection mediated by CD8* T cells against M. tuberculosis. Finally, Aim 4 will address whether CD8+ memory T cells are generated during chronic tuberculosis infection. The related questions of how bacterial persistence affects T cells memory and how pre-existing mycobacterial immunity alters the M. tuberculosis-specific immune response will also be determined. This proposal will directly assess how CFP10-specific CD8+ T cells contribute to host defense and how their function is modulated by immunity and disease.

由于全球范围内结核病造成的公共卫生问题变得更加严重艾滋病流行和结核分枝杆菌多重耐药菌株的出现。为了解决这个问题结核病是世界性的祸害，开发结核病疫苗是国际优先事项。对M的细胞免疫。结核病对于控制感染至关重要，CD4”和 CD8+ T 细胞都很重要。因为 CD8+ T 细胞是结核病免疫所必需的，人们对引发结核病的疫苗策略非常感兴趣结核分枝杆菌特异性 CD8+ T 细胞。然而，评估 CD8+ T 细胞在宿主抵抗中的作用和由于 I 类 MHC 呈递的分枝杆菌抗原很少，疫苗诱导的免疫受到阻碍已被识别。因此，即使是关于 M 期间 CD8+ T 细胞功能的基本问题。结核感染仍然没有答案。我们已经鉴定出 CFP10 蛋白的一个表位，即呼吸道结核分枝杆菌感染后小鼠肺部高达 30% 的 CD8+ T 细胞可识别感染。 CFP10 基因位于分枝杆菌基因组的 RD1 区域内，这是分枝杆菌基因组必需的对于结核分枝杆菌的毒力，CFP10 很可能是分枝杆菌的毒力因子。此外，它是免疫反应的主要目标，大多数感染结核分枝杆菌的人都患有结核分枝杆菌。 B 细胞和 T 细胞对 CFP10 抗原免疫的证据。我们建议研究 CFPiO-的作用特异性 CD8+ T 细胞对结核分枝杆菌的免疫。在目标 1 中，体内 CD8+ T 细胞的分子基础 - 将确定介导的细胞毒性。这些结果将确定 CTL 是否在 M 期间启动。结核感染通过细胞毒性颗粒胞吐作用、CD95/95L 途径或其他途径杀死靶细胞机制。我们还将讨论受感染的巨噬细胞是否在体内被杀死。目标2地址疫苗接种引发的 CFP10 特异性 CD8+ T 细胞是否可以保护小鼠免受呼吸道挑战结核分枝杆菌。接种 CFP10 疫苗的小鼠将受到结核分枝杆菌的攻击，以及 CFP10- 特定的 CD8+ T 细胞在挑战后做出反应，以及这些 T 细胞是否有助于宿主抵抗被确定。目标 3 将具体确定细胞毒性活性或其他 IFNy 独立性 CD8* T 细胞介导的针对结核分枝杆菌的保护需要这些功能。最后，目标 4 将解决慢性结核感染期间是否产生 CD8+ 记忆 T 细胞的问题。相关的细菌持久性如何影响 T 细胞记忆以及预先存在的分枝杆菌免疫力如何等问题结核分枝杆菌特异性免疫反应的改变也将被确定。该提案将直接评估 CFP10 特异性 CD8+ T 细胞如何促进宿主防御以及它们的功能如何受到调节免疫力和疾病。