HELPER T CELL REGULATION IN MURINE LEISHMANIASIS

鼠利什曼病的辅助 T 细胞调节

• 批准号: 6124358
• 负责人: STEVEN L REINER
• 金额: $ 32.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6124358
• 关键词: Leishmania major; MHC class II antigen; T cell receptor; antigen presentation; cell death; cofactor; cytokine; flow cytometry; gene mutation; helper T lymphocyte; host organism interaction; interferon gamma; interleukin 4; laboratory mouse; leishmaniasis; leukocyte activation /transformation; macrophage; microorganism immunology; molecular pathology; oligonucleotides; tissue /cell culture

Leishmaniasis and many other parasitic diseases remain a major cause of world-wide morbidity and mortality. A central regulatory event in the defense against parasitic diseases is the post-thymic maturational fate of CD4+ (helper) T cells. Murine infection with Leishmania major has a well-defined sequence of cellular events. These features make it a versatile model to study the molecular regulation of CD4+ T cells in vivo. First, the parasite invades mammalian macrophages. Class II- restricted helper T cells become activated and expand after the presentation of parasite antigens. The maturing helper T cells assume one of two developmental fates. The Th1 fate results in control of infection while the Th2 fate results in disseminated disease. Resolution of infection involves elimination of the parasite as well as the host's own formerly-useful immune cells. This proposal will systematically define the molecular events regulating the activated life and death of CD4+ T cells during murine infection with L. major. The proposal has three specific aims. The experimental methods rely on in vivo infection of normal and mutant mice and are complemented by in vitro cellular and molecular analyses of macrophages and T cells. The first aim will provide a detailed assessment of MHC class II-restricted antigen presentation in macrophages. The influence which antigen presentation has on T cell function during infection will be examined. Additionally, the interactive functions of two MHC class II cofactors, invariant chain and DM, will be assessed by infection of mice deficient in these molecules. The second aim examines the regulation of helper T cell lineage commitment by defining the cytokine and non-cytokine factors which influence maturational fate and, thus, disease outcome. In addition, a novel hypothesis regarding the molecular basis for T helper subset commitment will be tested using murine leishmaniasis as model system. The third aim will analyze the homeostatic elimination of parasite-specific T cells which is necessary to avert the potentially pathological consequences of an immune reaction. Cell death molecules which are responsible for killing CD4+ T cells during leishmaniasis will be identified by analysis of loss-of-function mutations. The results of these studies should provide important regulatory information about the control of helper T cells during an immune response. Since many infectious and autoimmune conditions are mediated by the heterogeneous life and death of CD4+ T cells, this should ultimately result in improved treatment for diseases.

利什曼病和许多其他寄生虫病仍然是 世界范围内的发病率和死亡率。一次中央监管活动在 对寄生虫病的防御是胸腺成熟后的命运 CD4+(辅助)T细胞。小鼠感染大利什曼原虫 一系列明确的细胞事件。这些功能使其成为 研究CD_4~+T细胞分子调控的通用模型 活着。首先，这种寄生虫入侵哺乳动物的巨噬细胞。第II类- 受限制的辅助性T细胞在 寄生虫抗原的呈现。成熟的辅助T细胞假定 两种发展命运之一。Th1的命运导致了对 感染，而Th2的命运导致播散性疾病。分辨率 感染包括消灭寄生虫和寄主的 拥有以前有用的免疫细胞。这项建议将系统地 定义调节激活的生命和死亡的分子事件 小鼠感染梅毒后的CD_4~+T细胞这项提案已经 三个具体目标。实验方法依赖于体内感染。 正常小鼠和突变小鼠，并辅以体外细胞和 巨噬细胞和T细胞的分子分析。第一个目标是 提供MHC第二类限制性抗原的详细评估 在巨噬细胞中呈现。对抗原呈递的影响 感染过程中对T细胞功能的影响将被检测。另外， 两个MHC II类余因子的相互作用函数，不变链 和DM，将通过感染缺乏这些基因的小鼠来评估 分子。第二个目的是研究辅助性T细胞的调节 定义细胞因子和非细胞因子的血统承诺 它们会影响成熟的命运，从而影响疾病的结局。在……里面 关于辅助性T细胞分子基础的新假说 亚集承诺将以小鼠利什曼病为模型进行测试 系统。第三个目标将分析动态平衡的消除 寄生虫特异性T细胞是避免潜在的 免疫反应的病理后果。细胞死亡分子 在利什曼病期间杀死CD4+T细胞的人将 通过对功能丧失突变的分析来鉴定。结果是 这些研究应该提供重要的监管信息 在免疫反应过程中对辅助T细胞的控制。因为有很多人 感染和自身免疫状况是由异种病毒介导的 CD4+T细胞的生死，这最终应该会导致 改善对疾病的治疗。