WASp家族Verprolin同源蛋白WAVE2调节T细胞免疫稳态和抗原特异性免疫应答的机制研究

批准号:
31970841
项目类别:
面上项目
资助金额:
59.0 万元
负责人:
张劲翼
依托单位:
学科分类:
适应性免疫
结题年份:
2023
批准年份:
2019
项目状态:
已结题
项目参与者:
张劲翼
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中文摘要
WAVE2是WASp家族主要成员之一,与自身免疫性疾病和神经退行性疾病的发生高度相关。由于缺乏WAVE2在免疫细胞中缺失的动物模型,对WAVE2在T细胞中的作用尚不清楚。为此,我们构建了WAVE2在T细胞中条件性基因敲除小鼠。前期工作发现,WAVE2缺失小鼠表现出多器官炎症和自身免疫病症状。WAVE2缺失T细胞高度活化,增殖和分化异常。WAVE2缺失T细胞经TCR/CD28刺激后mTOR及下游效应分子高度激活,糖酵解和葡萄糖摄取水平上升以及线粒体活化。慢性mTOR活化还导致T细胞活性氧分子生成增加、线粒体功能下降、T细胞耗竭和抗原免疫应答下降。抑制mTOR活性可逆转WAVE2缺失T细胞的激活状态以及WAVE2缺失小鼠的系统性炎症。因此,我们的研究首次揭示了WAVE2通过抑制PI3K/AKT/mTOR通路的活性以及mTOR依赖性的代谢重新编程调控T细胞免疫稳态和适应性免疫应答的关键机制。
英文摘要
The significance of actin remodeling to immune system has been highlighted by the identification of mutations of gene encoding Wiskott-Aldrich syndrome protein (WASp) causing primary immunodeficiency Wiskott-Aldrich syndrome and pivotal roles identified for WASp in many fundamental T cell processes and effector functions (Matalon et al., 2013). However, immunomodulatory functions of other WASp family proteins are less studied. Here we show ablation of WASp family verprolin homologous subgroup protein 2 (WAVE2), a member of WASp protein family in T cells resulted in progressive splenomegaly and lymphadenopathy and multi-organ inflammation. WAVE2 ablation provoked aberrant T cell activation, accelerated homeostatic proliferation, effector differentiation and impaired antigen-specific immune response. Mechanistically, WAVE2 interacts with and restrains the mechanistic target of rapamycin (mTOR) signaling and loss of WAVE2 leads to constitutive mTOR activation, metabolic reprogramming and mitochondrial activation of naïve T cells. Chronic mTOR activation also causes mitochondrial insufficiency and compromised fitness in activated T cells, dumping antigen specific immune response. Inhibition of mTOR signaling restores T-cell quiescence and functionality of WAVE2-deficient T cells and alleviate inflammation of WAVE2-deficient mice. Connectively, our findings reveal that WAVE2 plays an essential role in maintaining T-cell quiescence, homeostasis and adaptive immunity, at least in part, via restraining the mTOR signaling.
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DOI:10.1038/s41421-023-00625-0
发表时间:2024-01-09
期刊:CELL DISCOVERY
影响因子:33.5
作者:Lei, Wen;Zhao, Ai;Liu, Hui;Yang, Chunmei;Wei, Cheng;Guo, Shanshan;Chen, Zhilu;Guo, Qunyi;Li, Linjie;Zhao, Mingzhe;Wu, Gongqiang;Ouyang, Guifang;Liu, Ming;Zhang, Jinyi;Gao, Jimin;Qian, Wenbin
通讯作者:Qian, Wenbin
细胞骨架调节蛋白WAVE2维护免疫耐受及抑制自身免疫的机制研究
- 批准号:32270940
- 项目类别:面上项目
- 资助金额:54万元
- 批准年份:2022
- 负责人:张劲翼
- 依托单位:
国内基金
海外基金
