Function of microRNAs in controlling regulatory T cell biology

摘要 维持正常的Foxp3+调节性T细胞(Treg)的动态平衡和抑制功能对于 建立免疫耐受性。最近，一类短的调节性非编码RNA也被称为 MicroRNAs(MiRNAs)在Treg细胞的发育和功能中起着关键作用。最近我们有 研究表明，选择性地去除Treg细胞中的miRNAs导致自身免疫致死性的早期发生 与在缺乏Treg细胞的小鼠身上观察到的结果无法区分。不同的miRNA表达谱， 在Treg细胞中许多被Foxp3直接靶向的基因进一步表明特定的miRNAs可以控制 Treg生物学的不同方面。为此，需要Foxp3驱动的miR-155来维持正常的Treg细胞 正如我们之前的研究所证明的那样，动态平衡。在本申请中，我们已经证明了高miR-146a Treg细胞中的表达是通过靶向信号转导有效控制TH1反应的关键 和激活子转录因子1(STAT1)。Treg细胞中miR-146a的丢失导致两种总水平的升高 和磷酸化的STAT1。结果，带有miR-146a缺陷Treg细胞的小鼠死于 干扰素依赖型I型免疫病理学。我们目前的结果提供了强有力的证据表明，在 除了Treg细胞的动态平衡外，Treg抑制功能也可以受到单个miRNA的调节。这 研究进一步表明，依赖于miRNA的转录后调控使Treg细胞能够控制 特定类型的效应器T细胞反应。 我之前的研究涉及使用广泛的分子和细胞手段来研究两者 通过各种未经处理的小鼠品系和 临床适用的模型包括同种异体移植和不同的肿瘤系统。在鲁登斯基医生的指导下 目前的指导和斯隆-凯特琳癌症纪念医院提供的丰富和足智多谋的环境 中心和三机构生物医学研究社区的其他成员，包括威尔·康奈尔医学 学院和洛克菲勒大学，我提议进行一项多方面的研究，利用遗传学、生化、 免疫学方法和全动物实验研究miRNA依赖的作用 Treg细胞介导的免疫耐受的转录后调控。与全面的 职业发展计划，包括建立机构内和机构间合作以及继续培训 和教育，这些因素无疑将促进我向独立研究的过渡，并应该允许 我想成为世界顶级研究机构之一的一名久负盛名的研究员。

Summary Maintaining normal Foxp3+ regulatory T (Treg) cell homeostasis and suppressive function is essential for establishing immunological tolerance. Recently, a class of short regulatory non-coding RNAs also called as microRNAs (miRNAs) are shown to be pivotal in the development and function of Treg cells. Recently we have shown that selectively ablation of miRNAs in Treg cells resulted in the early onset of autoimmune lethality indistinguishable to those that were observed in mice devoid of Treg cells. Distinct miRNA expression profiles, of which many were directly targeted by Foxp3 in Treg cells further suggested specific miRNAs could control different facets of Treg biology. To this end, Foxp3-driven miR-155 is required for maintaining normal Treg cell homeostasis as demonstrated in our previous study. In this application, we have shown that high miR-146a expression in Treg cells is essential for effective controls of TH1 responses through targeting signal transducer and activator transcription 1 (STAT1). Loss of miR-146a in Treg cells resulted in increased levels of both total and phosphorylated STAT1. As a consequence, mice with miR-146a deficient Treg cells succumbed to IFN¿-dependent type I immunopathology. Our current results provided strong evidence suggesting that, in addition to homeostasis in Treg cells, Treg suppression function could also be regulated by a single miRNA. This work further implied that miRNA-dependent post-transcriptional regulation enables Treg cells to control a particular type of effector T cell responses. My previous research involved employing a wide spectrum of molecular and cellular means to study both humoral and cellular immune responses through both a variety of unmanipulated mouse strains and clinical-applicable models including allograft transplantation and different tumor systems. Under Dr. Rudensky's current mentoring and with the rich and resourceful environment provided by Memorial Sloan-Kettering Cancer Center and other members in the Tri-institutional biomedical research community including Weill Cornell Medical College and The Rockefeller University, I propose a multifaceted study employing genetic, biochemical, immunological approaches and whole animal experimentation to examine the role of miRNA-dependent post-transcriptional regulation in Treg cell-mediated immunological tolerance. Together with a comprehensive career development plan, including establishing intra- and inter-institutional collaborations and continued training and education, these elements will undoubtedly facilitate my transition to independent research and should allow me to become a well-established investigator in one of the world's top-research institutes.