mTOR Signaling Regulates Protective Activity of Transferred CD4+Foxp3+ T Cells in Repair of Acute Kidney Injury
mTOR Signaling Regulates Protective Activity of Transferred CD4+Foxp3+ T Cells in Repair of Acute Kidney Injury
复制标题
DOI：
10.4049/jimmunol.1601251
复制
发表时间：
2016-11-15
影响因子：
4.4
通讯作者：
Chen, Huihui
中科院分区：
文献类型：
--
作者：
Chen, Guochun;Dong, Zheng;Chen, Huihui
CD 4（+）Foxp 3（+）调节性T细胞（TCRs）是正常免疫稳态所必需的。最近的研究表明，Treg转移促进急性肾损伤（阿基）的恢复，但过继转移后维持Treg功能的分子事件仍不清楚。本研究旨在研究Treg介导的对缺血性阿基的治疗作用中哺乳动物雷帕霉素靶蛋白（mTOR）信号转导的调节。我们注意到C57 BL/6小鼠肾脏中的Treg显著扩增，在肾缺血/再灌注后具有增强的免疫抑制能力。mTOR抑制显著增加了培养的CD 4（+）T细胞中的TcR的频率，增加了抗炎细胞因子的产生，相反，mTOR激活减少了抗炎细胞因子的产生。在缺血/再灌注手术之前，将雷帕霉素（一种mTOR抑制剂）瞬时给予C57 BL/6小鼠。由于雷帕霉素对肾小管再生的抑制作用，在阿基的早期恢复中未观察到雷帕霉素治疗的有益作用。然而，雷帕霉素显著增强了肾脏THP的扩张，增加了抗炎细胞因子的mRNA表达。雷帕霉素处理的TCRs的连续转移显著抑制常规T细胞、应答髓样细胞和反应性肌成纤维细胞;然而，它促进宿主TCRs和替代巨噬细胞，导致更好的肾功能和更少的肾纤维化。总之，Treg转移与mTOR抑制显著改善缺血性阿基的结局。这些发现揭示了mTOR信号传导在过继转移后维持Treg活性方面的重要作用，并突出了靶向TcR在急性和慢性肾脏疾病中的治疗潜力。
CD4(+)Foxp3(+) regulatory T cells (Tregs) are required for normal immune homeostasis. Recent studies suggested that Treg transfer facilitates recovery from acute kidney injury (AKI), but the molecular events that maintain Treg function after adoptive transfer remain unclear. This study aimed to investigate the regulation of mammalian target of rapamycin ( mTOR) signaling in the Treg-mediated therapeutic effect on ischemic AKI. We noted significant Treg expansion in C57BL/6 mouse kidney, with enhanced immunosuppressive capacity after renal ischemia/reperfusion. mTOR inhibition significantly increased the frequency of Tregs in cultured CD4(+) T cells, with enhanced production of anti-inflammatory cytokines, which, conversely, was reduced by mTOR activation. Rapamycin, an inhibitor of mTOR, was transiently administered to C57BL/6 mice before ischemia/reperfusion surgery. No beneficial effect of rapamycin treatment was seen in the early recovery of AKI as a result of its inhibitory effect on tubular regeneration. However, rapamycin markedly enhanced the expansion of kidney Tregs, with increased mRNA expression of anti-inflammatory cytokines. Adoptive transfer of rapamycin-treated Tregs markedly suppressed conventional T cells, responder myeloid cells, and reactive myofibroblasts; however, it promoted host Tregs and alternative macrophages, leading to better renal function and less kidney fibrosis. Taken together, Treg transfer with mTOR inhibition markedly improves outcomes of ischemic AKI. These findings reveal an important role for mTOR signaling in maintaining Treg activity after adoptive transfer and highlight the therapeutic potential of targeting Tregs in acute and chronic kidney disease.