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

• 批准号: 7019743
• 负责人: SAMUEL M BEHAR
• 金额: $ 40万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-15 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7019743
• 关键词: CD95 molecule; MHC class I antigen; MHC class II antigen; Mycobacterium tuberculosis; active immunization; antigen antibody reaction; bacterial genetics; cell mediated cytotoxicity; cell mediated lymphocytolysis test; cytolysins; cytoprotection; cytotoxic T lymphocyte; exocytosis; genetically modified animals; host organism interaction; immune response; immunologic memory; interferon gamma; laboratory mouse; macrophage; microorganism immunology; pore forming protein; transfection /expression vector; tuberculosis; tuberculosis vaccines; virulence

DESCRIPTION (provided by applicant): 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 CFP10specific 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 IFNg-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.

描述（由申请人提供）：由于全球艾滋病流行和结核分枝杆菌多重耐药菌株的出现，结核病造成的公共卫生问题变得更加严重。为了对抗这一全球性祸害，开发结核病疫苗是国际优先事项。针对结核分枝杆菌的细胞免疫对于控制感染至关重要，CD4+ 和 CD8+ T 细胞都很重要。由于 CD8+ T 细胞是结核病免疫所必需的，因此人们对引发结核分枝杆菌特异性 CD8+ T 细胞的疫苗策略非常感兴趣。然而，由于很少鉴定出 I 类 MHC 呈递的分枝杆菌抗原，因此评估 CD8+ T 细胞在宿主抵抗力和疫苗诱导免疫中的作用受到了阻碍。因此，即使是关于结核分枝杆菌感染过程中 CD8+ T 细胞功能的基本问题仍然没有答案。我们已经鉴定出 CFP10 蛋白的一个表位，在呼吸道结核分枝杆菌感染后，小鼠肺部中高达 30% 的 CD8+ T 细胞可以识别该表位。 CFP10基因位于分枝杆菌基因组的RD1区域内，这是结核分枝杆菌毒力所必需的，并且CFP10很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都有针对 CFP10 抗原的 B 和 T 细胞免疫的证据。我们建议研究 CFP10 特异性 CD8+ T 细胞在结核分枝杆菌免疫中的作用。在目标 1 中，将建立体内 CD8+ T 细胞介导的细胞毒性的分子基础。这些结果将确定结核分枝杆菌感染期间引发的 CTL 是否通过细胞毒性颗粒胞吐作用、CD95/95L 途径或其他机制杀死靶细胞。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 探讨疫苗接种引发的 CFP10 特异性 CD8+ T 细胞是否可以保护小鼠免受结核分枝杆菌的呼吸道感染。接种 CFP10 疫苗的小鼠将受到结核分枝杆菌的攻击，并且将确定 CFP10 特异性 CD8+ T 细胞在攻击后如何反应，以及这些 T 细胞是否有助于宿主抵抗。目标 3 将具体确定 CD8+ T 细胞介导的针对结核分枝杆菌的保护是否需要细胞毒活性或其他 IFNg 独立功能。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。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如何改变结核分枝杆菌特异性免疫反应等相关问题也将得到确定。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免疫和疾病的调节。