Translational Reprogramming by Regulatory T Cells

项目摘要 调节性T细胞在维持自身抗原免疫耐受中起着不可或缺的作用 以及通过施加抑制程序来抑制对宿主有害的过度免疫反应 朝向各种各样的目标免疫细胞。然而，介导这一过程的细胞内分子事件 对靶细胞的抑制仍然知之甚少。在这项研究中，我们将研究分子性质 这一抑制方案的中心假设是，调节翻译机制和特定的 信使核糖核酸的翻译控制是这次重新编程事件的核心。我们将利用一种新的遗传工具 允许在体外和体内免疫中几乎任何免疫细胞类型的核糖体的免疫提纯 名为“RiboTag.”的模型使用RiboTag，我们将捕获全基因组的翻译组(所有mRNA都是 在Treg依赖的免疫耐受崩溃期间)。我们将进一步 研究这种mRNA转录本特异性翻译控制的机制，假设 反式作用的翻译调节蛋白因子在Tregs遇到的靶细胞中进行调节。这个 核糖体的免疫纯化和基于质谱学的蛋白质组学将 描述由核糖体本身或核糖体相关因子赋予的核蛋白质组中的这种变化 特雷格在目标牢房遇到了。这些研究将在理解新的基因层方面开辟新的天地。 由Tregs实施的表达控制，Tregs是我们免疫系统中的关键组件，对于免疫学来说是必不可少的 宽容。

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.