CD4+ T Cell Receptors in Leishmaniasis

利什曼病中的 CD4 T 细胞受体

基本信息

批准号：
7147430
负责人：
Richard M Locksley
金额：
$ 32.32万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-06-15 至 2008-06-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7147430
关键词：
Animals Biochemical Biological Assay Biology CD4 Positive T Lymphocytes Cells Characteristics Cytokine Receptors Data Disease Effector Cell Elements Generations Genes Genetic Programming Genetic Transcription Green Fluorescent Proteins Helper-Inducer T-Lymphocyte Homeostasis Host Defense IL4 gene Immune Immune response Immune system Immunity Immunology In Vitro Infection Inflammatory Interferon Type II Interferons Interleukin-4 Investigation Learning Leishmania major Leishmaniasis Link Literature Lymphoid Mediating Messenger RNA Modeling Molecular Mouse Strains Mus Natural Killer Cells Nippostrongylus Organ Outcome Parasites Pathway interactions Peripheral Phosphorylation Physiological Play Polyribosomes Population Process Production Protein Secretion Proteins Receptor Signaling Recruitment Activity Regulation Regulatory Element Reporter Reporting Research Rest Shapes Signal Pathway Signal Transduction Site Stress T-Cell Receptor T-Lymphocyte TCR Activation Testing Th2 Cells Tissue Differentiation Tissues Transcript Translating Translations Upper arm Viral Work biological adaptation to stress cell type cytokine eosinophil immunopathology in vitro Assay in vivo infectious disease model insight interest lymph nodes mRNA capping neoplastic novel novel strategies programs response transcription factor upstream kinase

项目摘要

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 knockin 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.

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，协调宿主防御和免疫病理学。许多免疫学研究都集中在细胞上淋巴器官或体外分化过程中。当前的兴趣越来越集中在外围设备上组织，效应细胞在其中执行其功能。使用带有敲入结构的小鼠，忠实地记录细胞因子转录本，我们发现幼稚辅助 T 细胞，当极化以表达特定细胞因子时，维持细胞中 IL-4 和 IFN-γ 转录物处于非翻译状态，我们将其定义为“平衡”。重新激活可以快速翻译先前转录的信息，从而促进快速和灵活回应。该提案旨在确定正常初始 T 细胞启动的程度这种在细胞因子转录物水平上的“平衡”效应状态；研究有助于的机制保持“平衡”状态；并使用特征明确的鼠寄生虫感染模型 - 包括巴西圆线虫和大型利什曼原虫 - 确定体内是否存在相关途径。该提案将使用多种转基因小鼠以及分子和生化检测以确定 T 细胞分化所使用的过程是否被支架到更一般的细胞上协调翻译与蛋白质分泌水平波动的途径。天真的研究结果分化的辅助 T 细胞将与组织中驻留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。这样的分析可以允许之间进行广泛的比较激活 IFN-γ 基因、IL-4 基因或这两种基因的不同细胞类型，可能揭示核心遗传程序与免疫系统中的效应器功能密切相关。