WASP通过影响膜IL-2R簇集内吞调节Treg发育与功能

WAS综合征由细胞骨架蛋白调节因子WASP基因突变引起，自身免疫突出难治且机制不明。调节性T细胞(Treg)通过维持外周免疫耐受广泛参与自身免疫病理生理，IL2-IL2R-STAT5信号通路在Treg发育及功能中必不可少。前期发现WAS患者及WASP敲除鼠Treg亚群与功能显著异常，胞膜IL2R蛋白降低，mRNA转录正常；首次发现WASP缺陷Treg胞膜IL2R内吞增加，提示WASP可能影响胞膜IL2R簇集内吞调节IL2-IL2R-STAT5信号传导从而影响Treg发育与功能。本研究以课题组优势WAS患者队列和长期研究为基础，结合已构建的WASP敲除和Treg条件性WASP敲除鼠模型，探讨细胞骨架蛋白在Treg胞膜细胞因子受体IL2R蛋白调控中的功能，首次阐释WASP协同N-WASP通过细胞骨架重构调节Treg膜IL2R簇集内吞的新机制，寻找以Treg为目标的WAS患者自身免疫治疗新靶点。

Wiskott-Aldrich syndrome (WAS) is caused by WASP mutation. Autoimmune of WAS patients is prevalent and hard to control but the mechanism is not fully elucidated. Regulatory T cells (Treg) are important for maintaining peripheral immune tolerance and preventing autoimmunity. IL-2-IL-2R-STAT5 signaling pathway is essential in Treg development and function maintenance. In previous study we have get some clue of Treg deficiency in WAS patient and WASP knock out mouse model. (1) Treg subsets were skewed and suppression function was decreased; (2) The STAT5 phosphorylation level of Treg cells from WASP knockout mice were decreased with IL-2 activation ex vivo; (3) The IL-2R protein on Treg cell membrane was decreased in WAS patients, but the mRNA expression was normal; (4) IL-2R on Treg cell membrane was degraded by endocytosis after clustering, and IL-2R degradation increase in WASP knockout mice. These data indicate that WASP, as an important cytoskeleton reconstruction regulator, may regulate IL-2-IL-2R-STAT5 signal by affecting the membrane clustering and endocytosis of IL-2R, thus regulating Treg development and function maintenance. Based on the cohort of WAS patients and long-term research in the field, this study combined the established WASP knockout and Treg conditional WASP knockout mouse models to explore the role of cytoskeleton proteins in the regulation of Treg membrane cytokine receptor IL-2R protein homeostasis, aiming to explain the new mechanism of WASP work with N-WASP regulating IL-2R clustering and endocytosis through cytoskeleton reconstruction for the first time, and find new targets for autoimmunotherapy in WAS patients targeting Treg.