CD4+ T Cell Receptors in Leishmaniasis

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适应性T细胞的产物，协调宿主防御和免疫病理。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。目前的兴趣越来越集中在外周组织，在那里效应细胞执行其功能。使用具有敲入结构的小鼠，忠实地记录细胞因子转录，我们发现幼稚的辅助T细胞，当极化表达特定细胞因子时，将细胞中的IL-4和ifn - γ转录维持在非翻译状态，我们将其定义为“平衡”。再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。本提案试图定义正常初始T细胞的启动在细胞因子转录水平上建立这种“平衡”效应状态的程度；研究有助于维持“平衡”状态的机制；并使用具有良好特征的小鼠寄生虫感染模型——包括巴西尼波圆线虫和主要利什曼原虫——来确定相关途径是否在体内存在。该提案将使用各种转基因小鼠以及分子和生化分析来确定分化T细胞所使用的过程是否被支架在更一般的细胞途径上，以协调蛋白质分泌水平波动的翻译。在幼稚和分化的辅助T细胞中发现的结果将与驻留在组织中的效应细胞群进行比较，包括NK细胞、NK T细胞和嗜酸性粒细胞。这种分析可能允许在激活ifn - γ基因、IL-4基因或两种基因的不同细胞类型之间进行广泛的比较，潜在地揭示与免疫系统效应功能密切相关的核心遗传程序。

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.