CD4+ T Cell Receptors in Leishmaniasis

描述(由申请人提供)：效应者免疫主要由细胞因子介导，细胞因子是先天的和分化的适应性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中的细胞或在体外分化过程中。目前人们的兴趣越来越集中在周围组织上，效应细胞在那里执行它们的功能。利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，当极化以表达特定的细胞因子时，在细胞中保持IL-4和干扰素-伽马转录的未翻译状态，我们将其定义为“稳定的”。重新激活导致对先前转录的消息的快速翻译，从而促进快速和灵活的反应。这项建议旨在定义正常的幼稚T细胞在多大程度上在细胞因子转录本水平上建立这样一种“稳定”的效应状态；研究有助于维持这种“稳定”状态的机制；并使用具有良好特征的小鼠寄生虫感染模型--包括巴西尼波斯特线虫和大利什曼原虫--来确定相关的途径是否存在于体内。该提案将使用各种转基因小鼠，以及分子和生化分析，以确定分化T细胞所使用的过程是否建立在更一般的细胞途径上，以协调翻译和蛋白质分泌水平的波动。在幼稚和分化的辅助T细胞中的发现将与驻留在组织中的效应细胞群体进行比较，包括NK细胞、NK T细胞和嗜酸性粒细胞。这样的分析可能会对激活干扰素-伽马基因和/或IL-4基因的不同细胞类型进行广泛的比较，潜在地揭示与免疫系统中的效应器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.