Extracellular vesicles from mesenchymal stem cells prevent contact hypersensitivity through the suppression of Tc1 and Th1 cells and expansion of regulatory T cells
Extracellular vesicles from mesenchymal stem cells prevent contact hypersensitivity through the suppression of Tc1 and Th1 cells and expansion of regulatory T cells
复制标题
间充质干细胞的细胞外囊泡通过抑制 Tc1 和 Th1 细胞以及扩增调节性 T 细胞来预防接触性超敏反应
DOI：
10.1016/j.intimp.2019.05.048
复制
发表时间：
2019-09-01
影响因子：
5.6
通讯作者：
Weng, Jianyu
中科院分区：
文献类型：
--
作者：
Guo, Liyan;Lai, Peilong;Weng, Jianyu
间充质干细胞(MSC-EVS)分泌的细胞外小泡(EVS)作为免疫调节剂和抗炎药受到越来越多的重视。我们研究了MSC-EVS对变态反应性接触性皮炎(ACD)的治疗效果，ACD是一种典型的T细胞介导的疾病。建立接触性超敏反应(CHS)小鼠ACD模型，静脉注射MSC-EVS治疗。我们发现，人脐血MSC-EVS可以显著预防CHS的病理改变，包括减少耳廓肿胀和白细胞渗透。注射MSC-EVS可显著抑制CD8(+)干扰素-γ(+)细胞毒性T细胞(Tc1)和CD4(+)干扰素-γ(+)1型辅助T细胞(Th1)，降低促炎性肿瘤坏死因子-α(TNT-α)和干扰素-γ(干扰素-γ)水平，诱导CD4(+)CD25(+)Foxp3(+)调节性T细胞(Tregs)和抗炎IL-10水平。在体外，MSC-EVS还抑制Tc1和Th1细胞，诱导Tregs和相关细胞因子，进一步表明MSC-EVS的免疫调节作用。有趣的是，PKH26标记的MSC-Evs被发现直接被CD3(+)T细胞内化，导致体外信号转导和转录激活因子1(STAT1)蛋白水平降低。综上所述，MSC-EVS在体内外通过抑制Tc1和Th1免疫应答，诱导Tregs表型，从而预防CHS的发生。MSC-EV影响CD3(+)T细胞的机制可能部分涉及体外靶向STAT1。因此，MSC-EVS是ACD等T细胞介导性疾病无细胞免疫调节治疗的理想候选细胞。
Extracellular vesicles (EVs) secreted by mesenchymal stem cells (MSC-EVs) are taken more seriously as immunomodulatory and anti-inflammatory agents. We studied the therapeutic effects of MSC-EVs on allergic contact dermatitis (ACD), a typical T cell-mediated disorder. A contact hypersensitivity (CHS) mouse model for ACD was established and treated by intravenous MSC-EVs injection. We found that human umbilical cord MSC-EVs could significantly prevent the pathology of CHS, including reduced ear swelling and leukocyte infiltration. Injection of MSC-EVs significantly inhibited CD8(+) IFN-gamma(+) cytotoxic T (Tc1) cells and CD4(+) IFN-gamma(+) type 1 helper T (Th1) cells, and reduced the level of pro-inflammatory Tumor Necrosis Factor-alpha (TNT-alpha) and interferon gamma (IFN-gamma), and induced CD4(+) CD25(+)Foxp3(+) regulatory T cells (Tregs) and the level of anti-inflammatory IL-10. In vitro, MSC-EVs also suppressed Tc1 and Th1 cells and induced Tregs and the related cytokines, further indicating the immune regulatory role of MSC-EVs. Interestingly, PKH26-labeled MSC-EVs were found to be directly internalized by CD3(+) T cells, resulting in reduced signal transducer and activator of transcription 1 (STAT1) protein levels in vitro. In summary, MSC-EVs can prevent the onset of CHS by inhibiting Tc1 and Th1 immune responses and inducing the Tregs phenotype in vivo and in vitro. The mechanism by which MSC-EVs influence CD3(+) T cells might partially involve targeting STAT1 in vitro. Therefore, MSC-EVs are ideal candidates for cell-free immunomodulatory therapy for T cell-mediated diseases such as ACD.