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，结核病提出的公共卫生问题变得更加严重 AIDS流行和结核分枝杆菌的多药抗性菌株的出现。对抗这一点全球祸害，结核病的疫苗开发是国际优先事项。细胞免疫对M。结核病对于控制感染至关重要，CD4”和CD8+ T细胞都很重要。 CD8+ T细胞是对结核病的免疫所必需的，对引起的疫苗策略引起了极大的兴趣结核特异性CD8+ T细胞。但是，评估CD8+ T细胞在宿主电阻中的作用和疫苗诱导的免疫力受到了阻碍已经确定了。因此，即使是有关CD8+ T细胞功能的基本问题。结核病感染仍未得到解答。我们已经确定了CFP10蛋白的表位在呼吸道性分枝杆菌后，多达30％的CD8+ T细胞在小鼠的肺中识别感染。 CFP10基因位于分枝杆菌基因组的RD1区域内，这是必需的对于结核分枝杆菌的毒力，CFP10可能是分枝杆菌毒力因子。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具有 B和T细胞对CFP10抗原的免疫的证据。我们建议研究CFPIO- 特异性CD8+ T细胞可免疫结核分枝杆菌。在AIM 1中，体内CD8+ T细胞的分子基础将建立介导的细胞毒性。这些结果将确定CTL是否在M中进行了启动。结核病感染通过细胞毒性颗粒胞吐作用，CD95/95L途径或另一种杀死靶细胞机制。我们还将解决是否在体内杀死感染的巨噬细胞。 AIM 2地址疫苗接种引起的CFP10特异性CD8+ T细胞是否可以保护小鼠免受呼吸挑战结核分枝杆菌。 CFP10接种疫苗的小鼠将受到结核分枝杆菌的挑战，以及CFP10-如何特定的CD8+ T细胞在挑战之后做出反应，以及这些T细胞是否有助于宿主电阻可以确定。 AIM 3将明确确定细胞毒性活性还是其他非依赖性的活性由CD8* T细胞介导的结核分枝杆菌介导的保护需要功能。最后，AIM 4将解决了在慢性结核病感染期间是否产生CD8+记忆T细胞。相关细菌持久性如何影响T细胞记忆以及如何预先存在分枝杆菌免疫的问题也将确定结核分枝杆菌特异性免疫反应。该提议将直接评估CFP10特异性CD8+ T细胞如何有助于宿主防御以及如何调节其功能免疫和疾病。