Translational Reprogramming by Regulatory T Cells

调节性 T 细胞的翻译重编程

• 批准号: 9765776
• 负责人: Ram Savan
• 金额: $ 27.29万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-04 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765776
• 关键词: Affinity Chromatography; Antigen-Presenting Cells; Autoantigens; Autoimmune Diseases; Bioinformatics; Biological; Biological Assay; Biology; CD4 Positive T Lymphocytes; Cells; Cellular Structures; Cessation of life; Clustered Regularly Interspaced Short Palindromic Repeats; Critical Pathways; DNA; DNA Sequence Alteration; Data; Development; Epitopes; Eragrostis; Event; FOXP3 gene; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Translation; Human; Immune; Immune Targeting; Immune Tolerance; Immune response; Immune system; Immunological Models; In Vitro; Link; Luciferases; Mass Spectrum Analysis; Mediating; Messenger RNA; Modeling; Molecular; Molecular Biology Techniques; Mus; Mutagenesis; Nature; Pathway interactions; Play; Proteins; Proteomics; RNA; Regulation; Regulatory Element; Regulatory T-Lymphocyte; Reporter; RiboTag; Ribosomal Proteins; Ribosomes; Role; Signal Pathway; Specificity; Syndrome; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic Intervention; Thymus Gland; Time; Trans-Activators; Transcript; Transgenic Mice; Translating; Translational Regulation; Translations; Untranslated Regions; base; biological systems; cell type; central tolerance; cis acting element; design; effector T cell; experimental study; genetic information; genetic regulatory protein; genome-wide; in vivo; insight; mouse model; novel; peripheral tolerance; prevent; programs; recruit; stem; tool; transcriptomics; translation factor; translatome; virtual

Project Summary Regulatory T cells (Tregs) play an indispensable role in maintaining immunological tolerance to self-antigens and in suppressing excessive immune responses deleterious to the host by exerting a suppressive program towards a wide variety of target immune cells. However, the intracellular molecular events that mediate such suppression in target cells in still poorly understood. In this study, we will investigate the molecular nature of this suppression program with the central hypothesis that regulation of the translational machinery and specific mRNA translation control is at the core of this reprogramming event. We will utilize a novel genetic tool that allows immunopurification of ribosomes in virtually any immune cell type in both in vitro and in vivo immune models called ‘RiboTag.’ Using RiboTag, we will capture the genome-wide translatome (all mRNAs being translated in time and space) during Treg-dependent immunological tolerance breakdown. We will further investigate the mechanism of such mRNA transcript-specific translation control with the hypothesis that the trans-acting translation regulatory protein factors are modulated in target cells encountered by Tregs. The RiboTag mediated immunopurification of ribosomes followed by mass spectrometry based proteomics will delineate such changes in the riboproteome (the ribosome itself or ribosome-associated factors) endowed by Treg encounter in target cells. These studies will break new ground in understanding a novel layer of gene expression control imposed by Tregs, a critical component in our immune system essential for immunological tolerance.

项目概要 调节性T细胞（Treg）在维持对自身抗原的免疫耐受中发挥着不可或缺的作用 并通过实施抑制程序来抑制对宿主有害的过度免疫反应 然而，介导此类的细胞内分子事件有多种。 对靶细胞的抑制作用仍知之甚少。在这项研究中，我们将研究其分子性质。 这个抑制程序的中心假设是翻译机制的调节和特定的 mRNA 翻译控制是该重编程事件的核心，我们将利用一种新颖的遗传工具。 允许在体外和体内免疫中对几乎任何免疫细胞类型的核糖体进行免疫纯化 模型称为“RiboTag”。使用 RiboTag，我们将捕获全基因组翻译组（所有 mRNA 在 Treg 依赖性免疫耐受崩溃期间，我们将进一步研究。 研究这种 mRNA 转录特异性翻译控制的机制，假设 Tregs 遇到的靶细胞中的反式作用翻译调节蛋白因子受到调节。 RiboTag 介导的核糖体免疫纯化，随后基于质谱的蛋白质组学将 描述核糖蛋白质组（核糖体本身或核糖体相关因子）的此类变化 这些研究将为理解新的基因层开辟新天地。 Tregs 施加的表达控制是我们免疫系统中的关键组成部分，对于免疫学至关重要 宽容。