CD4+ T Cell Receptors in Leishmaniasis

利什曼病中的 CD4 T 细胞受体

• 批准号: 6673246
• 负责人: Richard M Locksley
• 金额: $ 17.04万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6673246
• 关键词: Leishmania major; T cell receptor; biological signal transduction; cell differentiation; disease /disorder proneness /risk; enzyme linked immunosorbent assay; flow cytometry; genetically modified animals; green fluorescent proteins; helper T lymphocyte; laboratory mouse; leishmaniasis; microarray technology; microorganism immunology; parasite infection mechanism; polymerase chain reaction; tissue /cell culture; western blottings

DESCRIPTION (provided by the applicant): Effector immunity is mediated largely by cytokines, products of innate and differentiated adaptive T cells that orchestrate both host defense and immunopathology. Much research in immunology has focused on cells in lymphoid organs or during in vitro differentiation. Current interest has increasingly focusing on peripheral tissues, where effector cells carry out their functions. Using mice with knock-in constructs that faithfully record cytokine transcripts, we find that naive helper T cells, when polarized to express specific cytokines, maintain IL-4 and IFN-gamma transcripts in an untranslated state in the cell, which we define as 'poised'. Reactivation leads to rapid translation of the previously transcribed message, facilitating rapid and flexible responses. This proposal seeks to define the extent to which priming of normal naive T cells establishes such a 'poised' effector state at the level of cytokine transcripts; to investigate mechanisms that contribute to maintaining the 'poised' state; and to use well-characterized murine parasite infection models - including Nippostrongylus brasiliensis and Leishmania major - to establish whether the relevant pathways exist in vivo. The proposal will use a variety of genetically modified mice together with molecular and biochemical assays to establish whether the process used by differentiating T cells is scaffolded onto more general cellular pathways for coordinating translation with fluctuating levels of protein secretion. Findings made in naive and differentiated helper T cells will be compared with effector cell populations that are resident in tissues, including NK cells, NK T cells and eosinophils. Such analysis may allow broad comparisons between different cell types that activate the IFN-gamma gene, the IL-4 gene, or both genes, potentially revealing core genetic programs linked intimately with effector function in the immune system.

描述（由申请人提供）：效应免疫主要由细胞因子介导，细胞因子是先天和分化的适应性T细胞的产物，它们协调宿主防御和免疫病理学。免疫学的许多研究都集中在淋巴器官或体外分化过程中的细胞。目前的兴趣越来越多地集中在外周组织，其中效应细胞执行其功能。使用具有忠实地记录细胞因子转录物的敲入构建体的小鼠，我们发现初始辅助T细胞在极化以表达特定细胞因子时，将IL-4和IFN-γ转录物维持在细胞中的非翻译状态，我们将其定义为“定位”。重新激活导致先前转录的信息的快速翻译，促进快速和灵活的反应。该提案旨在定义正常幼稚T细胞的引发在细胞因子转录水平上建立这种“平衡”效应状态的程度;调查有助于维持“平衡”状态的机制;并使用充分表征的鼠寄生虫感染模型-包括巴西日圆线虫和利什曼原虫-以确定相关途径是否存在于体内。该提案将使用各种转基因小鼠以及分子和生物化学测定来确定分化T细胞所使用的过程是否被支架化到更一般的细胞途径上，以协调翻译与蛋白质分泌水平的波动。将在初始和分化的辅助T细胞中获得的发现与驻留在组织中的效应细胞群体（包括NK细胞、NK T细胞和嗜酸性粒细胞）进行比较。这种分析可以允许在激活IFN-γ基因、IL-4基因或这两种基因的不同细胞类型之间进行广泛比较，从而潜在地揭示与免疫系统中的效应子功能密切相关的核心遗传程序。