miRNA-mediated control of regulatory T cell development and function - a role for miR-181

适应性免疫系统处于微妙的平衡状态，一方面可以有效地对抗传染性病原体，另一方面可以耐受无害的抗原和自身抗原。这种平衡的破坏可能会导致过敏或自身免疫性疾病。调节性T细胞(Treg细胞)构成了一种主要的耐受性T细胞群，能够抑制不想要的免疫反应，这种免疫反应的丧失伴随着致命的自身免疫。然而，Treg细胞的过度活动也可能构成对癌症免疫反应低效的潜在原因。Treg细胞可以在胸腺中产生(nTreg细胞)，也可以从外周的幼稚细胞产生(iTreg细胞)。控制nTreg细胞发育的机制还不完全清楚。有人认为nTreg细胞本质上是自体反应的，因此接收不同强度和可能持续时间的TCR信号。MicroRNAs(MiRNAs)是一种小分子调控RNA，主要通过转录后抑制多种靶基因发挥作用。Treg细胞的发育和功能关键依赖于miRNA的存在。然而，单个miRNAs在这些过程中的作用仍然难以捉摸。我们最近发现miR-181a/b-1关键控制着不变自然杀伤T细胞的产生，自然杀伤T细胞遵循与Treg细胞非常相似的发育途径。因此，我们假设miR-181a/b-1调控nTreg细胞的发育。为了验证这一假设，我们产生了miR-181a/b-1缺陷的小鼠。利用这个新的小鼠模型，我们计划在这个项目中解决以下问题：miR-181a/b-1控制Treg细胞发育的机制是什么？MiR-181a/b-1是如何控制Treg细胞功能的？最后，我们将通过一种公正的方法来补充这一建议，以确定新的miR-181靶基因。综上所述，该项目将阐明由miRNA控制的Treg细胞发育和功能的分子机制。因此，我们的研究可能为定向操纵Treg细胞以恢复疾病耐受性和自身免疫之间的平衡开辟新的途径。

The adaptive immune system is finely balanced to efficiently fight infectious pathogens on the one hand and to tolerate innocuous antigen as well as self-antigen on the other hand. Disruption of this balance may result in allergy or autoimmune disease. Regulatory T cells (Treg cells) constitute a major tolerogenic T population capable of suppressing an unwanted immune response, whose loss is accompanied by fatal autoimmunity. However, excessive action of Treg cells may also constitute an underlying cause of inefficient immune responses against cancer. Treg cells can be generated in the thymus (nTreg cells) or from naïve cells in the periphery (iTreg cells). The mechanisms controlling development of nTreg cells are only incompletely understood. It has been suggested that nTreg cells are essentially auto-reactive and, therefore, receive TCR signals of different strength and possibly duration. MicroRNAs (miRNAs) are small regulatory RNAs, which function primarily through post-transcriptional repression of a wide variety of target genes. Development and function of Treg cells critically depend on the presence of miRNA. However, the role of individual miRNAs in these processes remains elusive. We have recently shown that miR-181a/b-1 critically controls the generation of invariant natural killer T cells, which follow a very similar developmental pathway as Treg cells. Thus, we hypothesize that miR-181a/b-1 regulates development of nTreg cells. In order to test this hypothesis, we have generated mice deficient in miR-181a/b-1. Employing this novel mouse model we plan to address the following questions in this project: What are the mechanisms by which miR-181a/b-1 controls development of Treg cells? How does miR-181a/b-1 control Treg cell function? Finally, we will complement this proposal by an unbiased approach to identify novel miR-181 target genes. Taken together, this project will shed light on the molecular mechanisms of Treg cell development and function controlled by miRNA. In consequence, our studies might open up new avenues for targeted manipulation of Treg cells to restore the balance between tolerance and autoimmunity in disease.