MicroRNAs 调控滤泡辅助型T细胞分化及免疫应答之研究

Germinal (GC) centers form in peripheral lymphoid organs and are responsible for clearance of invading pathogens and establishment of memory. Follicular helper T (TFH) cells, a new subset of helper T cells, provide helps to GC B cells during GC reaction through engagement of surface receptors and cytokine production, therefore promotes plasma cell differentiation and memory cell formation. MicroRNAs (miRNAs) have been reported that regulate TFH cell differentiation, germinal center reaction and immune responses. However, most of miRNAs may participate in regulating TFH cell differentiation and their functions are largely unknown and need to be clarified. We identified new miRNAs which are highly expressed in TFH cells, such as miR-155 by using miRNA expression profiling analysis. We found that miR-155 regulated TFH cell differentiation and functions through targeting Peli1. We will further study other highly expressed miRNAs in TFH cells and uncover the detailed molecular mechanisms underlies TFH and GC B cell differentiation and immune responses. Completion of our project will not provide us new insights into the regulation TFH cell differentiation by miRNAs, but also promote development of vaccine design and understand the pathogenesis of and chronic infection and autoimmune diseases.

生发中心在外周淋巴器官形成, 并且负责清除入侵的病原体及建立免疫记忆。滤泡辅助型T (TFH) 细胞能促进浆细胞的分化和记忆细胞的形成。MicroRNAs (miRNAs) 能调节TFH细胞和生发中心(GC) B细胞的分化及免疫应答。然而，大多数可能影响TFH细胞分化的miRNAs，它们的功能未知而且极待厘清。利用miRNA基因表达图谱分析, 我们已鉴定出在TFH细胞高表达的miR-155和其他miRNAs, 前期结果发现miR-155通过靶基因Peli1去调节TFH细胞的分化和功能。我们将研究其他在TFH细胞高表达miRNA是否影响滤TFH细胞和生发中心B细胞分化及免疫应答, 并探究它们如何调控TFH细胞和GC B细胞分化及免疫应答的分子机制。上述研究的完成miRNAs对TFH细胞的分化提供新的学理证明，同时有助于疫苗的发展及了解慢性感染和自身免疫病的致病机理。

生发中心在外周淋巴器官形成, 并且负责清除入侵的病原体及建立免疫记忆。滤泡辅助型T (TFH) 细胞透过表面受体的结合和细胞因子的产生, 以促进浆细胞的分化和记忆细胞的形成。MicroRNAs (miRNAs) 能调节TFH细胞和生发中心(GC) B细胞的分化及免疫应答。然而，大多数可能影响TFH细胞分化的miRNAs，它们的功能未知而且极待厘清。利用miRNA基因图谱分析, 我们已鉴定出在TFH细胞高表达的miR-155和其他miRNAs, 本项目的结果主要发现miR-155通过靶基因Peli1去调节TFH细胞的分化和功能。Peli1 是E3泛素化连接酶, 在T细胞主要降解c-Rel 蛋白, 调节活化T细胞的增殖和CD40L 表达。因此, miR-155敲除的T细胞, Peli1高表达导致c-Rel下调,.从而调节TFH细胞分化与增殖都下调, 造成生发中心B细胞分化及免疫应答的缺陷。上述研究的完成miR-155对TFH细胞的分化提供新的想法，同时有助于疫苗的发展及了解慢性感染和自身免疫病的致病机理。