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调节性T细胞中的AIM2抑制自身免疫性疾病
2021-01-29 16:58

美国北卡罗莱纳大学教堂山分校Jenny P.-Y. Ting、Yisong Y. Wan等研究人员合作发现,调节性T细胞中的AIM2抑制自身免疫性疾病。该项研究成果于2021年1月27日在线发表在《自然》杂志上。

研究人员发现,DNA结合的炎症小体受体AIM2在T调节(Treg)细胞的功能中具有T细胞内在的和炎症小体非依赖的作用。AIM2在人和小鼠Treg细胞中均高表达,并由TGFβ所诱导,其启动子被Treg细胞相关的转录因子(如RUNX1、ETS1、BCL11B和CREB)占据。RNA测序、生化和代谢分析表明AIM2减弱AKT磷酸化、mTOR和MYC信号转导以及糖酵解,但促进Treg细胞中脂质的氧化磷酸化。

从机理上讲,AIM2与RACK1-PP2A磷酸酶复合物相互作用来抑制AKT磷酸化。谱系追踪分析表明,AIM2在炎症过程中可促进Treg细胞的稳定性。尽管AIM2通常被认为是髓样细胞中的炎性小体效应分子,但这项研究结果表明AIM2的T细胞内在作用是通过减少AKT-mTOR信号传导和改变免疫代谢,进而增强Treg细胞的稳定性来抑制自身免疫。 

据介绍,炎性小体通过激活髓样细胞中的caspase-1和细胞焦亡来启动先天防御和炎症反应。它由先天性免疫受体/传感器、前胱天蛋白酶-1和常见的衔接子分子ASC组成。与它们的促炎功能一致,caspase-1、ASC和炎性小体成分NLRP3通过增强髓样细胞中IL-1β和IL-18的分泌来加剧实验性自身免疫性脑脊髓炎的自身免疫。

附:英文原文

Title: AIM2 in regulatory T cells restrains autoimmune diseases

Author: Wei-Chun Chou, Zengli Guo, Hao Guo, Liang Chen, Ge Zhang, Kaixin Liang, Ling Xie, Xianming Tan, Sara A. Gibson, Elena Rampanelli, Yan Wang, Stephanie A. Montgomery, W. June Brickey, Meng Deng, Leslie Freeman, Song Zhang, Maureen A. Su, Xian Chen, Yisong Y. Wan, Jenny P.-Y. Ting

Issue&Volume: 2021-01-27

Abstract: The inflammasome initiates innate defence and inflammatory responses by activating caspase-1 and pyroptotic cell death in myeloid cells1,2. It consists of an innate immune receptor/sensor, pro-caspase-1, and a common adaptor molecule, ASC. Consistent with their pro-inflammatory function, caspase-1, ASC and the inflammasome component NLRP3 exacerbate autoimmunity during experimental autoimmune encephalomyelitis by enhancing the secretion of IL-1β and IL-18 in myeloid cells3,4,5,6. Here we show that the DNA-binding inflammasome receptor AIM27,8,9,10 has a T cell-intrinsic and inflammasome-independent role in the function of T regulatory (Treg) cells. AIM2 is highly expressed by both human and mouse Treg cells, is induced by TGFβ, and its promoter is occupied by transcription factors that are associated with Treg cells such as RUNX1, ETS1, BCL11B and CREB. RNA sequencing, biochemical and metabolic analyses demonstrated that AIM2 attenuates AKT phosphorylation, mTOR and MYC signalling, and glycolysis, but promotes oxidative phosphorylation of lipids in Treg cells. Mechanistically, AIM2 interacts with the RACK1–PP2A phosphatase complex to restrain AKT phosphorylation. Lineage-tracing analysis demonstrates that AIM2 promotes the stability of Treg cells during inflammation. Although AIM2 is generally accepted as an inflammasome effector in myeloid cells, our results demonstrate a T cell-intrinsic role of AIM2 in restraining autoimmunity by reducing AKT–mTOR signalling and altering immune metabolism to enhance the stability of Treg cells.

DOI: 10.1038/s41586-021-03231-w

Source: nature.com/articles/s41586-021-03231-w

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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