外泌体选择性运载miR-155调控Tfh细胞介导CLL微环境免疫失衡的机制研究

微环境免疫失衡在慢性淋巴细胞白血病（CLL）发生发展过程中起关键作用，也是治疗难点。CLL患者存在滤泡辅助性T细胞（Tfh）数量增多及功能异常，但机制尚不清楚。我们前期工作发现Tfh细胞比例升高与CLL疾病预后不良相关，同时进展期患者肿瘤外泌体（Exo）中miR-155表达升高，而miR-155是对Tfh细胞分化起调控作用的关键microRNA。由此我们推测CLL细胞可能通过Exo传递miR-155影响Tfh细胞功能从而促进疾病进展。本项目拟在前期工作的基础上，以患者原代细胞、小鼠模型及细胞系为研究对象，进一步明确：①Exo高表达miR-155与CLL疾病进展及Tfh功能异常的相关性；②CLL细胞是否可通过Exo作用于Tfh细胞；③该影响是否通过传递miR-155作用于FOS基因所致。项目结果将进一步阐明CLL细胞与微环境免疫细胞的沟通机制，为改善CLL微环境免疫提供新的思路和实验室依据。

Microenvironmental immunodissonance plays a key role during occurrence and development of chronic lymphocytic leukemia(CLL) and remains the difficult bit waiting to be resolved at present. The T follicular helper(Tfh) cells in CLL patients are elevated and dysfunctional, the machanisms of which still remain unclear. Our previous work revealed the relevance of the increase of Tfh cells and inferior outcome of the disease, and we found that the expression of miR-155, a key microRNA regulating the differentiation of Tfh cells, was increased in the tumor-derived exosomes (Exo) from patients of progressive stage. Therefore, we presume that CLL cells might affect the function of Tfh cells by delivering exosomal miR-155, thus promoting disease progression. Based on the previous work and taking primary leukemia cells, a mouse model and cell lines as research objects, we are planning to further clarify: ①the relevance of overexpression of miR-155 in Exo with disease progression and Tfh cell dysfunction; ②whether CLL cells impact Tfh cells through Exo; ③ whether the impact of CLL-dirived Exo on Tfh cells is caused by miR-155 targeting FOS. The results will further illuminate the communication mechanisms between CLL cells and immune cells in the microenvironment and provide new methods and laboratory evidence to improve microenvironmental immunity in CLL.