HELPER T CELL REGULATION IN MURINE LEISHMANIASIS

鼠利什曼病的辅助 T 细胞调节

• 批准号: 2464628
• 负责人: STEVEN L REINER
• 金额: $ 19.82万
• 依托单位: UNIVERSITY OF CHICAGO
• 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/2464628
• 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导致疟疾的主要原因。 全球发病率和死亡率。 一个中心的监管事件， 抵抗寄生虫病是胸腺成熟后的命运 CD4+（辅助）T细胞。 小鼠感染硕大利什曼原虫， 一系列明确的细胞活动 这些特点使其成为 研究CD4+ T细胞分子调控的通用模型， vivo. 首先，寄生虫侵入哺乳动物的巨噬细胞。 第II类─ 限制性辅助性T细胞被激活，并在免疫后扩增。 寄生虫抗原的呈递。 成熟的辅助性T细胞假设 两种发展命运之一 Th1命运导致控制 感染，而Th2命运导致播散性疾病。决议 感染包括消除寄生虫以及宿主的 拥有以前有用的免疫细胞。 该提案将系统地 定义调节激活的生命和死亡的分子事件 小鼠感染L.少校 该提案 三个具体目标。 实验方法依赖于体内感染 正常和突变小鼠，并补充了体外细胞和 巨噬细胞和T细胞的分子分析。 第一个目标将 提供MHC II类限制性抗原的详细评估 在巨噬细胞中呈现。 抗原提呈的影响 在感染期间对T细胞功能的影响将被检查。 此外，本发明还 两个MHC II类辅因子的相互作用，不变链 和DM，将通过感染这些缺陷的小鼠来评估。 分子。 第二个目的是检查辅助性T细胞的调节 通过定义细胞因子和非细胞因子的谱系定型 影响成熟的命运，从而影响疾病的结果。 在 此外，一种新的假设，关于分子基础的T辅助细胞， 亚群定型将使用鼠利什曼病作为模型进行测试 系统 第三个目标将分析稳态消除 寄生虫特异性T细胞，这是必要的，以避免潜在的 免疫反应的病理后果。 细胞死亡分子 在利什曼病期间负责杀死CD4+ T细胞的细胞， 通过分析功能丧失突变来鉴定。 结果 这些研究应该提供重要的监管信息， 在免疫反应中控制辅助性T细胞。 由于许多 感染性和自身免疫性疾病是由异质性 CD4+ T细胞的生存和死亡，这最终会导致 改善疾病的治疗。