Translational Reprogramming by Regulatory T Cells

项目摘要 调节性T细胞在维持机体对自身抗原的免疫耐受中起着不可或缺的作用 以及通过施加抑制程序抑制对宿主有害的过度免疫应答 针对多种目标免疫细胞。然而，介导这种作用的细胞内分子事件 对靶细胞的抑制仍然知之甚少。在这项研究中，我们将调查的分子性质， 这种抑制程序的中心假设是，翻译机制的调节和特异性的 mRNA翻译控制是这一重编程事件的核心。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中的核糖体的免疫纯化。 名为“RiboTag”的模型。使用RiboTag，我们将捕获全基因组翻译组（所有mRNA都是 在时间和空间上翻译）。我们将进一步 研究这种mRNA转录特异性翻译控制的机制， 反式作用的翻译调节蛋白因子在Tclase遇到的靶细胞中被调节。的 核糖体的RiboTag介导的免疫纯化，随后是基于质谱的蛋白质组学， 描述核糖蛋白质组（核糖体本身或核糖体相关因子）的变化， Treg在靶细胞中相遇。这些研究将为理解一种新的基因层开辟新的天地。 由THBE施加的表达控制，THBE是我们免疫系统中对免疫调节至关重要的关键组分。 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.