Activated regulatory T-cells attenuate myocardial ischaemia/reperfusion injury through a CD39-dependent mechanism
Activated regulatory T-cells attenuate myocardial ischaemia/reperfusion injury through a CD39-dependent mechanism
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激活的调节性 T 细胞通过 CD39 依赖性机制减轻心肌缺血/再灌注损伤
DOI：
10.1042/cs20140672
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发表时间：
2015-05-01
期刊：
影响因子：
6
通讯作者：
Cheng, Xiang
中科院分区：
文献类型：
--
作者：
Xia, Ni;Jiao, Jiao;Cheng, Xiang
调节性T细胞(Tregs)通常被认为是关键的免疫调节剂，在各种免疫介导性疾病中维持免疫耐受并对抗组织损伤。然而，其在心肌缺血再灌注损伤(MIRI)中的作用仍不清楚。本研究的目的是确定Tregs是否对小鼠的MIRI有有益的影响。本研究通过耗竭调节性T细胞(DEREG)小鼠和Forkhead box P3(Foxp3)-GFP敲打小鼠过继转移的方法研究了Tregs在小鼠MIRI中的作用，并对其体内和体外心脏保护机制进行了进一步的研究。MIRI后，Tregs在小鼠心脏中迅速积聚。在DEREG小鼠模型中，选择性地耗尽Tregs会导致MIRI加重。相反，体外激活的Tregs的过继转移抑制了MIRI，而新鲜分离的Tregs则没有影响。机制上，激活的Treg介导的抗MIRI保护作用不能被白介素10或转化生长因子β(1)抑制而被分化簇39(CD39)的基因缺失所削弱。此外，过继转移体外激活的Tregs可减轻心肌细胞的凋亡，激活Akt和细胞外信号调节激酶(ERK)的促存活通路，并抑制中性粒细胞的浸润，CD39缺乏可抑制这一作用。最后，直接经皮冠状动脉介入治疗(PCI)后的急性心肌梗死(AMI)患者的外周血单个核细胞显示，Treg人群中的CD4(+)CD25(+)CD127(低)Tregs减少，而CD39(+)细胞相对增加。总之，我们的数据验证了Tregs在MIRI中的保护作用。此外，体外激活的Tregs通过CD39依赖的机制改善MIRI，代表了一种假定的治疗策略。
Regulatory T-cells (Tregs) are generally regarded as key immunomodulators that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. However, its role in myocardial ischaemia/reperfusion injury (MIRI) remains unknown. The purpose of the present study was to determine whether Tregs exert a beneficial effect on mouse MIRI. We examined the role of Tregs in murine MIRI by depletion using 'depletion of regulatory T-cell' (DEREG) mice and adoptive transfer using Forkhead box P3 (Foxp3)-GFP knockin mice and the mechanisms of cardio protection were further studied in vivo and in vitro. Tregs rapidly accumulated in murine hearts following MIRI. Selective depletion of Tregs in the DEREG mouse model resulted in aggravated MIRI. In contrast, the adoptive transfer of in vitro-activated Tregs suppressed MIRI, whereas freshly isolated Tregs had no effect. Mechanistically, activated Treg-mediated protection against MIRI was not abrogated by interleukin (IL)-10 or transforming growth factor (TGF)-beta(1) inhibition but was impaired by the genetic deletion of cluster of differentiation 39 (CD39). Moreover, adoptive transfer of in vitro-activated Tregs attenuated cardiomyocyte apoptosis, activated a pro-survival pathway involving Akt and extracellular-signal-regulated kinase (ERK) and inhibited neutrophil infiltration, which was compromised by CD39 deficiency. Finally, the peripheral blood mononuclear cells of acute myocardial infarction (AMI) patients after primary percutaneous coronary intervention (PCI) revealed a decrease in CD4(+)CD25(+)CD127(low) Tregs and a relative increase in CD39(+) cells within the Treg population. In conclusion, our data validated a protective role for Tregs in MIRI. Moreover, in vitro-activated Tregs ameliorated MIRI via a CD39-dependent mechanism, representing a putative therapeutic strategy.