摘要
调节性T细胞(Treg细胞)是一种特殊的免疫抑制性CD4+-T淋巴细胞亚群,具有维持机体免疫稳态的重要作用。有研究证实,促凋亡蛋白Bim参与Treg细胞功能的调控,但是还没有使用条件性敲除小鼠对Bim在Treg细胞中功能研究的报道,且Treg细胞中Bim发挥功能的机制也不清楚。已知Bim在衰老的Treg细胞中丰度下调,然而该过程在Treg细胞衰老过程中的具体作用尚不清楚。本研究中,作者繁育产生Foxp3Cre;Bimfl/fl条件性敲除小鼠,特异性在Treg细胞中敲除Bim。Foxp3Cre;Bimfl/fl小鼠可育,但是出现多器官炎性细胞浸润和免疫细胞的过度激活,这表明Bim可以调节Treg细胞免疫抑制功能。Bim缺失导致Treg细胞转录组变化,以及Ctla4基因和多个信号通路的下调。Treg细胞中Bim的缺失可以抑制胆管癌的增殖,并延长胆管癌小鼠的生存期。Bim缺失的Treg细胞,不能复现衰老Treg细胞的转录组变化,这表明Bim的下调可能是Treg细胞衰老过程中的下游事件。
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Acknowledgments
This work was supported by the National Natural Science Foundation of China (No. 82172699), the Zhejiang Provincial Natural Science Foundation of China (No. LY21H100005), and the Zhejiang Provincial Medical Health Science and Technology Project (Western Medicine) from Health Commission of Zhejiang Province (No. 2024KY093). The author thanks Prof. Xiaoming FENG (Peking Union Medical College, China), Prof. Mark GROUDINE (Fred Hutchinson Cancer Center, USA), and Prof. Xin CHEN (University of California, San Francisco, USA) for providing key materials. The author also thanks Chao BI and Yueting XING from Core Facilities, Zhejiang University School of Medicine, China for technical support.
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Contributions
Di WU designed and preformed experiments, analyzed data, and wrote the manuscript. The author has read and approved the final manuscript, and therefore, has full access to all the data in the study and take responsibility for the integrity and security of the data.
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Ethics declarations
Di WU declares no competing interests.
All institutional and national guidelines for the care and use of laboratory animals were followed. All animal experiments were approved by the Animal Ethics Committee of Zhejiang University (No. 17864, May 19, 2020).
Additional information
Materials and methods
Detailed materials and methods are provided in the electronic supplementary materials of this paper.
The microarray data generated in this study have been deposited in Gene Expression Omnibus under accession code GSE233231.
Supplementary information
Figs. S1–S5; Tables S1 and S2; Materials and methods
