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科学家发现抑制自身免疫的新分子
作者:小柯机器人 发布时间:2021/3/26 13:42:45

近日,加拿大西奈山医院Katherine A. Siminovitch、Jia Qu等研究人员合作发现,WAVE2抑制mTOR激活从而维持T细胞稳态并防止自身免疫。该项研究成果发表在2021年3月26日出版的《科学》杂志上。

研究人员表示,肌动蛋白细胞骨架调节蛋白在有效免疫应答表达中的重要作用,缺乏Wiskott-Aldrich综合征肌动蛋白调节蛋白(WASp)的患者会表现出免疫力下降。在肌动蛋白重排的其他WASp相关驱动程序中,WASp家族Verprolin同源蛋白2(WAVE2)主要在造血细胞中表达,并与T细胞粘附和免疫突触组织所需的细胞骨架重塑有关。 然而,WAVE2在调节控制免疫力的T细胞功能中的确切作用仍然未知。

研究人员发现,T细胞中Wave2的条件性敲除会引起严重的自身免疫,这与mTOR激活增加和代谢重编程有关,从而引起自发激活和外周T细胞的分化。这些小鼠还表现出抗原特异性T细胞应答减少,并出现抑制性受体表达增加、线粒体功能失调以及活化后细胞存活率降低相关的。从机制上讲,WAVE2直接与mTOR结合并通过阻止mTOR与RAPTOR(mTOR的调节相关蛋白)和RICTOR(mTOR的雷帕霉素不敏感伴侣)的相互作用来抑制其激活。mTOR药理抑制剂可改善T细胞缺陷和免疫调节异常。因此,WAVE2抑制mTOR激活是维持T细胞稳态从而支持适应性免疫反应和预防自身免疫的前提。

总之,这项发现确定了WAVE2在抑制T细胞活化和效应子分化中的关键作用。WAVE2对T细胞活化的抑制作用不是由T细胞受体介导的,而是由其对mTOR与RAPTOR和RICTOR结合的抑制作用介导的。因此,可以通过mTOR信号传导的药理抑制剂改善小鼠模型中的自身免疫表型。 

附:英文原文

Title: WAVE2 suppresses mTOR activation to maintain T cell homeostasis and prevent autoimmunity

Author: Ming Liu, Jinyi Zhang, Benjamin D. Pinder, Qingquan Liu, Dingyan Wang, Hao Yao, Yubo Gao, Aras Toker, Jimin Gao, Alan Peterson, Jia Qu, Katherine A. Siminovitch

Issue&Volume: 2021/03/26

Abstract: Cytoskeletal regulatory protein dysfunction has been etiologically linked to inherited diseases associated with immunodeficiency and autoimmunity, but the mechanisms involved are incompletely understood. Here, we show that conditional Wave2 ablation in T cells causes severe autoimmunity associated with increased mammalian target of rapamycin (mTOR) activation and metabolic reprogramming that engender spontaneous activation and accelerated differentiation of peripheral T cells. These mice also manifest diminished antigen-specific T cell responses associated with increased inhibitory receptor expression, dysregulated mitochondrial function, and reduced cell survival upon activation. Mechanistically, WAVE2 directly bound mTOR and inhibited its activation by impeding mTOR interactions with RAPTOR (regulatory-associated protein of mTOR) and RICTOR (rapamycin-insensitive companion of mTOR). Both the T cell defects and immunodysregulatory disease were ameliorated by pharmacological mTOR inhibitors. Thus, WAVE2 restraint of mTOR activation is an absolute requirement for maintaining the T cell homeostasis supporting adaptive immune responses and preventing autoimmunity.

DOI: 10.1126/science.aaz4544

Source: https://science.sciencemag.org/content/371/6536/eaaz4544

期刊信息
Science:《科学》,创刊于1880年。隶属于美国科学促进会,最新IF:41.037