Department of General Surgery, Tianjin Medical University General Hospital, No. 154, Anshan Road, Heping District, Tianjin 300052, China; Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, No. 218, Jixi Road, Shushan District, Hefei, Anhui 230022, China.
Department of Gastrointestinal Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, No. 79, Qingchun Road, Shangcheng District, Hangzhou, Zhejiang 310003, China.
Cell Immunol. 2021 Sep;367:104400. doi: 10.1016/j.cellimm.2021.104400. Epub 2021 Jun 26.
Regulatory T cells (Tregs) are indispensable for the maintenance of immune tolerance. The purpose of this study was to investigate the effect of the interaction of the lncRNA PVT1 and miR-146a on Treg autophagy and reveal the mechanism to alleviate transplant rejection. PVT1 and miR-146a expression levels were analyzed by qRT-PCR. Bioinformatic analysis and methylation profiling were used to determine the relationship between PVT1 and miR-146a. Altered autophagic status in Tregs was detected by western blotting. The effect of autophagy on Treg function was assessed in cell coculture in vitro and in animal models. Our results showed that PVT1 expression was reduced in Tregs during rejection and negatively correlated with miR-146a expression. Higher PVT1 expression was associated with higher autophagy in Tregs. Further, highly autophagic Tregs had stronger inhibitory effects on CD4 T cells in vitro, prolonged allograft survival and alleviated rejection in vivo. Mechanistic studies showed that overexpression of PVT1 enhanced TNF receptor-associated factor (TRAF) 6 expression by directly targeting miR-146a. MiR-146a overexpression reversed PVT1-induced Treg autophagy and inhibited PVT1-induced TRAF6 expression. The present study shows a novel regulatory pathway of the autophagy program that comprises PVT1, miR-146a, and TRAF6. Our findings may provide potential targets and new therapeutic strategies for transplant rejection.
调节性 T 细胞（Tregs）对于维持免疫耐受至关重要。本研究旨在探讨长链非编码 RNA PVT1 和 miR-146a 相互作用对 Treg 自噬的影响，并揭示减轻移植排斥反应的机制。通过 qRT-PCR 分析 PVT1 和 miR-146a 的表达水平。通过生物信息学分析和甲基化谱分析来确定 PVT1 和 miR-146a 之间的关系。通过 Western blot 检测 Treg 中自噬状态的改变。通过体外细胞共培养和动物模型评估自噬对 Treg 功能的影响。结果显示，在排斥反应期间 Tregs 中的 PVT1 表达减少，与 miR-146a 表达呈负相关。较高的 PVT1 表达与 Tregs 中的较高自噬水平相关。此外，高自噬的 Tregs 在体外对 CD4 T 细胞具有更强的抑制作用，延长同种异体移植物的存活时间，并减轻体内排斥反应。机制研究表明，过表达 PVT1 通过直接靶向 miR-146a 增强肿瘤坏死因子受体相关因子 6（TRAF6）的表达。miR-146a 过表达逆转了 PVT1 诱导的 Treg 自噬，并抑制了 PVT1 诱导的 TRAF6 表达。本研究显示了包含 PVT1、miR-146a 和 TRAF6 的自噬程序的新调节途径。我们的发现可能为移植排斥反应提供潜在的治疗靶点和新的治疗策略。
