Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.
Front Immunol. 2021 Apr 9;12:661338. doi: 10.3389/fimmu.2021.661338. eCollection 2021.
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.
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.
The mTOR deficiency promoted M-MDSC differentiation and enhanced intracellular autophagy levels and . 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.
mTOR deficiency enhances the immunosuppressive function of M-MDSCs and prolongs mouse cardiac allograft survival.
髓源性抑制细胞（MDSCs）可在移植模型中预防同种异体移植物排斥反应并诱导免疫耐受。先前的研究表明，抑制 mTOR 信号通路可通过促进 MDSC 扩增来增强 MDSC 在心脏移植（HTx）中的保护作用。此外，mTOR 抑制与自噬有关。本研究探讨了 mTOR 缺陷单核细胞来源的 MDSCs（M-MDSCs）在小鼠 HTx 中的保护机制。
通过生成髓系特异性 mTOR 条件性敲除小鼠来获得 mTOR M-MDSCs。通过流式细胞术和 T 细胞增殖试验测定 mTOR M-MDSCs 的增殖和免疫抑制功能。通过 Western blot 和电子显微镜测定 mTOR M-MDSC 内的自噬水平。对野生型（WT）和 mTOR M-MDSCs 进行 RNAseq 分析。建立同种异体 HTx 小鼠模型，并给予 WT 或 mTOR M-MDSCs 治疗。通过酶联免疫吸附试验、流式细胞术和免疫组织化学检测，确定 WT 和 mTOR M-MDSC 诱导的免疫耐受。
mTOR 缺失促进了 M-MDSC 的分化，并增强了细胞内自噬水平。mTOR 缺失还增强了 M-MDSC 的免疫抑制功能。此外，输注 WT 和 mTOR M-MDSCs 通过抑制 T 细胞活化和诱导调节性 T 细胞，延长了心脏同种异体移植物的存活时间，并在受体小鼠中建立了免疫耐受。
mTOR 缺失增强了 M-MDSC 的免疫抑制功能，并延长了小鼠心脏同种异体移植物的存活时间。
