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

适应性免疫系统是精细平衡的，一方面有效地对抗感染性病原体，另一方面耐受无害抗原和自身抗原。这种平衡的破坏可能导致过敏或自身免疫性疾病。调节性T细胞（Treg细胞）是一种主要的耐受性T细胞群，能够抑制不需要的免疫反应，其丧失伴随着致命的自身免疫。然而，Treg细胞的过度作用也可能构成对癌症免疫反应效率低下的潜在原因。Treg细胞可以产生于胸腺（nTreg细胞），也可以产生于外周naïve细胞（iTreg细胞）。控制nTreg细胞发育的机制尚不完全清楚。有研究表明，nTreg细胞本质上是自反应性的，因此接收不同强度和可能持续时间的TCR信号。MicroRNAs （miRNAs）是一种小的调控rna，主要通过转录后抑制多种靶基因发挥作用。Treg细胞的发育和功能严重依赖于miRNA的存在。然而，单个mirna在这些过程中的作用仍然难以捉摸。我们最近的研究表明，miR-181a/b-1对不变性自然杀伤T细胞的产生起着关键的控制作用，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调节nTreg细胞的发育。为了验证这一假设，我们产生了miR-181a/b-1缺失的小鼠。采用这种新型小鼠模型，我们计划在该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如何控制Treg细胞功能？最后，我们将通过一种无偏倚的方法来鉴定新的miR-181靶基因来补充这一建议。综上所述，该项目将揭示miRNA控制Treg细胞发育和功能的分子机制。因此，我们的研究可能为靶向操纵Treg细胞以恢复疾病中耐受性和自身免疫之间的平衡开辟了新的途径。

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.