LIVER MEMORY CD8 T CELLS IN PROTECTION TO MALARIA

肝脏记忆 CD8 T 细胞可预防疟疾

• 批准号: 7086113
• 负责人: Urszula Krzych
• 金额: $ 34.14万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7086113
• 关键词: Aedes; CD antigens; Plasmodium berghei; antigen antibody reaction; antigen presenting cell; apoptosis; cellular immunity; computer data analysis; confocal scanning microscopy; cytotoxic T lymphocyte; enzyme linked immunosorbent assay; flow cytometry; green fluorescent proteins; immunologic memory; interleukin 2; interleukin 4; laboratory mouse; liver function; malaria; natural killer cells; polymerase chain reaction; radiation immunosuppression; suppressor T lymphocyte; tissue /cell culture

DESCRIPTION (provided by applicant): Memory T cells are one of the cardinal features of antigen-specific immune responses elicited by infections or vaccinations. The persistence of antigen-specific memory T cells is inextricably linked to long-lasting protection because they can be recalled into a swift effector function, hence their importance in prophylactic immunization against pathogens. The long-term goal of this proposal is to gain insights into the mechanisms of maintenance and a recall of memory CDS T cells, considered the main effectors against pre-erythrocytic stage malaria infection. The mouse model of sterile and lasting protection induced by radiation-attenuated Plasmodium berghei sporozoites is an excellent system for addressing the issues surrounding memory CDS T cells. Our hypothesis is that protracted protection induced by attenuated sporozoites depends in part on a network of liver memory CDS T cell subsets, each representing a different phase of activation or differentiation, the balance of which is profoundly affected by the repository of liver-stage antigens and cytokines. The specific aims are: (1) To identify liver cells that contain the repository of liver-stage antigens for the maintenance of memory CDS T cells. The localization of radiation-attenuated P. berghei parasites in the liver will be determined by the use of green fluorescence protein-parasites in combination with flow cytometry, confocal and electron microscopy. Liver and spleen cells will be tested for their role as antigen presenting cells. Mouse strains with specific genetic defects, such as the absence of certain cytokine or disrupted antigen processing pathway, will be used to confirm the antigen processing and presentation mechanisms. (2) To elucidate mechanisms of antigen presentation for recall and/or maintenance of liver memory CDS T cells. These studies will be conducted in vivo and in vitro and will focus on the identification of the antigen presenting cells, co-stimulatory molecules, CD27:CD70, CD40:CD40L, and 1- 4BB:1-4BBL, as well as cytokines, IL-7 and IL-15, that are needed to maintain memory CDS T cells. The results from these investigations will significantly enhance our understanding of memory CDS T cell response, which is a key element for consideration in the development of vaccines to prevent or abate malaria and other infectious diseases.

描述(由申请人提供)：记忆T细胞是感染或接种疫苗引起的抗原特异性免疫反应的基本特征之一。抗原特异性记忆T细胞的持久性与长期保护密不可分，因为它们可以被召回到快速的效应器功能中，因此它们在预防免疫中对病原体具有重要意义。这项建议的长期目标是深入了解记忆CDS T细胞的维持和召回机制，CDS T细胞被认为是对抗红细胞前期疟疾感染的主要效应者。伯氏疟原虫子孢子诱导的无菌和持久保护的小鼠模型是解决围绕记忆CDS T细胞的问题的极好系统。我们的假设是，减毒的子孢子诱导的持久保护部分依赖于肝记忆CDS T细胞亚群的网络，每个亚群代表不同的激活或分化阶段，其平衡受到肝期抗原库和 细胞因子。其具体目的是：(1)鉴定含有肝期抗原库的肝细胞，以维持记忆性CDS T细胞。利用绿色荧光蛋白寄生虫结合流式细胞术、共聚焦和电子显微镜，将确定辐射致弱伯氏疟原虫在肝脏中的定位。将测试肝和脾细胞作为抗原提呈细胞的作用。具有特定遗传缺陷的小鼠品系，如缺乏某些细胞因子或抗原处理途径中断，将被用于确认抗原处理和呈递机制。(2)阐明抗原提呈对回忆和/或维持肝记忆CDS T细胞的作用机制。这些研究将在体内和体外进行，重点是鉴定维持记忆CDS T细胞所需的抗原提呈细胞、共刺激分子CD27：CD70、CD40：CD40L和1-4BB：1-4BBL以及细胞因子IL-7和IL-15。这些研究的结果将大大提高我们对记忆CDS T细胞反应的理解，这是在开发预防或减轻疟疾和其他传染病的疫苗时考虑的关键因素。