The mTOR Deficiency in Monocytic Myeloid-Derived Suppressor Cells Protects Mouse Cardiac Allografts by Inducing Allograft Tolerance.
The mTOR Deficiency in Monocytic Myeloid-Derived Suppressor Cells Protects Mouse Cardiac Allografts by Inducing Allograft Tolerance.
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单核细胞骨髓源性抑制细胞中 mTOR 缺陷通过诱导同种异体移植耐受来保护小鼠同种异体心脏移植物
DOI：
10.3389/fimmu.2021.661338
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发表时间：
2021
影响因子：
7.3
通讯作者：
Rong R
中科院分区：
文献类型：
--
作者：
Li J;Chen J;Zhang M;Zhang C;Wu R;Yang T;Qiu Y;Liu J;Zhu T;Zhang Y;Rong R
背景 骨髓源性抑制细胞（MDSC）可以预防移植模型中的同种异体移植排斥并诱导免疫耐受。先前的研究表明，抑制mTOR信号传导可以通过促进MDSC扩张来增强心脏移植（HTx）中MDSC的保护作用。此外，mTOR抑制与自噬有关。本研究调查了小鼠 HTx 中 mTOR 缺陷的单核细胞 MDSC（M-MDSC）的保护机制。方法 生成骨髓特异性 mTOR 条件敲除小鼠以获得 mTOR−/− M-MDSC。通过流式细胞术和 T 细胞增殖测定确定 mTOR−/− M-MDSC 的增殖和免疫抑制功能。使用蛋白质印迹和电子显微镜测定 mTOR−/− M-MDSC 细胞内自噬水平。对野生型 (WT) 和 mTOR−/− M-MDSC 进行 RNAseq 分析。建立同种异体 HTx 小鼠模型并用 WT 或 mTOR−/− M-MDSC 治疗。进行酶联免疫吸附测定、流式细胞术和免疫组织化学测定以确定 WT 和 mTOR−/− M-MDSC 诱导的免疫耐受。结果 mTOR 缺陷促进 M-MDSC 分化并增强体内和体外细胞内自噬水平。 mTOR 缺陷还增强了 M-MDSC 的免疫抑制功能。此外，输注 WT 和 mTOR−/− M-MDSC 可延长心脏同种异体移植物的存活率，并通过抑制 T 细胞活化和诱导调节性 T 细胞在受体小鼠中建立免疫耐受。结论 mTOR缺陷可增强M-MDSCs的免疫抑制功能，延长小鼠同种异体心脏移植物的存活时间。
Background Myeloid-derived suppressor cells (MDSCs) can prevent allograft rejection and induce immune tolerance in transplantation models. Previous studies have demonstrated that inhibition of mTOR signaling can enhance the MDSC protective effect in heart transplantation (HTx) by promoting MDSC expansion. In addition, mTOR inhibition is related to autophagy. The present study investigated the protective mechanism of mTOR-deficient monocytic MDSCs (M-MDSCs) in mouse HTx. Methods Myeloid-specific mTOR conditional knockout mice were generated to obtain mTOR−/− M-MDSCs. The proliferation and immunosuppressive function of mTOR−/− M-MDSCs were determined by flow cytometry and T cell proliferation assays. The mTOR−/− M-MDSC intracellular autophagy levels were determined using western blotting and electron microscopy. RNAseq analysis was performed for wild-type (WT) and mTOR−/− M-MDSCs. Allogeneic HTx mouse model was established and treated with WT or mTOR−/− M-MDSCs. Enzyme-linked immunosorbent assay, flow cytometry, and immunohistochemistry assays were performed to determine WT and mTOR−/− M-MDSC-induced immune tolerance. Results The mTOR deficiency promoted M-MDSC differentiation and enhanced intracellular autophagy levels in vivo and in vitro. mTOR deficiency also enhanced the immunosuppressive function of M-MDSCs. In addition, infusing with WT and mTOR−/− M-MDSCs prolonged cardiac allograft survival and established immune tolerance in recipient mice by inhibiting T cell activation and inducing regulatory T cells. Conclusion mTOR deficiency enhances the immunosuppressive function of M-MDSCs and prolongs mouse cardiac allograft survival.
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影响因子：
10.1
作者：
Gabrilovich DI
通讯作者：
Gabrilovich DI
影响因子：
15.9
作者：
Alissafi, Themis;Hatzioannou, Aikaterini;Verginis, Panayotis
通讯作者：
Verginis, Panayotis
影响因子：
5.5
作者：
Parker, Katherine H.;Horn, Lucas A.;Ostrand-Rosenberg, Suzanne
通讯作者：
Ostrand-Rosenberg, Suzanne
影响因子：
4.6
作者：
Ueda, Yo;Saegusa, Jun;Morinobu, Akio
通讯作者：
Morinobu, Akio
影响因子：
7.3
作者：
Guri Y;Nordmann TM;Roszik J
通讯作者：
Roszik J