长链非编码RNA调控调节性T细胞发育与功能的机理研究

调节性T细胞（Treg）对于维持机体免疫平衡和耐受至关重要。长链非编码RNA（lncRNA）参与T细胞激活、分化及调控，在Treg细胞中有特征性表达谱。我们发现在Treg特异性敲除Usp21小鼠中,Th1型免疫反应明显强于正常对照小鼠；而Treg特异性敲除Med23小鼠脂肪组织中Treg细胞比例显著降低；两种敲除小鼠中Treg细胞发育正常。高通量测序证实在Usp21-/- Treg、Med23-/- Treg中存在几十或几百个lncRNAs表达异常；也有上百个lncRNA在基因敲除和对照Treg细胞中均高表达。基于小鼠表型和lncRNA表达谱，本课题将重点研究这些这些特征性lncRNA在Treg抑制Th1型免疫反应，组织特异性Treg调控机制；以及共同高表达的lncRNA在炎症条件下对Treg分化及稳态的调控，从而为重大免疫相关疾病诊治提供新靶点和新线索。

Regulatory T cells are essential in maintaining immune balance and self-tolerance. It is reported that lncRNAs regulate the differentiation of Th1，Th2 and Th17 cells. The expression profiles of lncRNAs in Treg cells are specific. We indicate that Usp21 stabilizes the function of Treg cells via acting as a deubiquitinase of GATA3. Med23 is one of the co-expression genes of Usp21 which is important for the activation of Teff cells. Knock out of Usp21 in Treg cells disturbers Th1 cell induced inflammation in mice. The percentage of Med23-/- Treg cells is much lower in the adipose tissue. The development of Treg cells is normal in these two types of knockout mice. The RNA-seq data indicate that there are 87 lncRNAs down regulated and 221 lncRNAs up regulated in Usp21-/- Treg cells. While in the Med23-/- Treg cells, 51 lncRNAs are down regulated and 42 lncRNAs are up regulated. And more than one hundred lncRNAS are high expressed in both knockout and normal Treg cells. On the basis of our previous study, we will further analysis the mechanisms underlying how these deregulated lncRNAs regulate the phenotype of Treg cells in the knock out mice and how high expressed lncRNAs regulate the differentiation and function of Treg cells under inflammatory conditions. This study will lay a basis on the better understanding of regulatory network in Treg cells and provide new clues for the treatment of important human diseases.