泛素连接酶Fbw7调节ILC2细胞发育和功能的机制研究

Innate lymphoid cells are a newly identified group of innate immune cells that play key roles in the immune defense against pathogens as well as contributing to tissue repair and inflammation. Group 2 ILCs have the capability to produce type 2 cytokines such as IL-5 and IL-13, thus participate in allergic inflammation, anti-helminth immunity, airway epithelial repair, and metabolic homeostasis. Protein ubiquitination is a novel means of post-transcriptional modification which involves in many aspects of cell biology, such as cell cycle, cell death, signal transduction, immune responses and inflammation. The F-box family E3 ligase Fbw7 forms an Skp1-cullin1-F box protein (SCF) complex that mediates the ubiquitination of substrates. We have previously identified that conditional Fbw7 depletion results in defects in the development of bone marrow ILC2s. We will dissect the cellular and molecular mechanisms of Fbw7 in the development and function of ILC2s, by using in vitro culture system for ILC2 differentiation and lung inflammation model, with the help of RNA-seq and protein mass spectrometry.

天然淋巴细胞（ILC）是一类新近定义的固有免疫细胞，在机体抗病原体固有免疫应答、组织重塑以及炎症反应中发挥重要作用。二型天然淋巴细胞（ILC2）能够分泌Th2型细胞因子如IL-5和IL-13，参与过敏性炎症反应、抵抗寄生虫感染、表皮细胞损伤修复及维持机体代谢稳态。蛋白质的泛素化是生物体内重要的蛋白质翻译后修饰过程,可以影响细胞周期、细胞凋亡、信号传导、免疫反应和炎症过程等多种生命活动。F-box家族蛋白Fbw7是一种E3泛素连接酶，通过形成SCF复合物介导底物的泛素化修饰。利用条件性基因敲除模型，我们发现Fbw7缺失会导致骨髓ILC2细胞的发育缺陷。我们将利用体外诱导ILC2分化体系和小鼠肺部炎症模型，结合转录组测序和蛋白质谱分析技术，揭示Fbw7调节ILC2细胞发育和功能的具体分子机制。

二型天然淋巴细胞（ILC2）是一类常驻于黏膜组织器官的固有免疫细胞，分泌二型细胞因子，包括IL-5和IL-13等，在过敏性炎症、组织修复、代谢稳态和宿主对蠕虫感染的防御等多种生理过程中发挥重要作用。利用条件性基因敲除小鼠，我们发现E3泛素连接酶Fbw7缺失导致小鼠多器官ILC2细胞表型异常，包括ILC2常驻的骨髓和小肠中ILC2细胞显著减少，而外周多个极少能检测到ILC2的器官中出现ILC2细胞异常定植，揭示Fbw7对ILC2细胞组织特异性的调控作用。Fbw7缺失导致ILC2细胞成熟水平升高，并促进其迁移。此外，Fbw7缺失影响外周组织中ILC2细胞的效应功能，损伤ILC2细胞介导的抗蠕虫感染免疫反应，导致机体清除寄生虫能力障碍。