A Unique Population of Regulatory T Cells in Heart Potentiates Cardiac Protection From Myocardial Infarction
A Unique Population of Regulatory T Cells in Heart Potentiates Cardiac Protection From Myocardial Infarction
复制标题
心脏中独特的调节性 T 细胞群可增强心脏对心肌梗死的保护
DOI：
10.1161/circulationaha.120.046789
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发表时间：
2020-11-17
期刊：
影响因子：
37.8
通讯作者：
Cheng, Xiang
中科院分区：
文献类型：
--
作者：
Xia, Ni;Lu, Yuzhi;Cheng, Xiang
背景：调节性T细胞（Tregs），传统上被认为是免疫反应的有效抑制因子，由于其第二个主要功能：驻留在实质组织和维持局部稳态，越来越受到关注。然而，所谓的组织treg在心脏中的存在、独特的表型和功能尚不清楚。方法：在小鼠心肌梗死（MI）、心肌缺血/再灌注损伤和心脏冷冻损伤模型中，监测损伤心肌中Tregs的动态积累。采用大体积RNA测序分析心肌梗死或缺血再灌注损伤后心肌treg的转录组学特征。利用光转化、异种共生、单细胞t细胞受体测序和过继性转移来确定心脏Tregs的来源。在功能分析中进一步评估了白细胞介素-33/抑制致瘤性2轴和Sparc（分泌酸性富半胱氨酸糖蛋白）的作用，Sparc是一种在心脏Tregs中上调的分子。结果：我们发现心肌梗死、缺血再灌注损伤和低温损伤小鼠心肌中Tregs高度富集。转录组学数据显示，从受伤心脏中分离的Tregs与它们的淋巴细胞对照物（包括心脏引流淋巴结）相比，具有大量差异表达的转录物，具有促进梗死修复的表型，表明了一种独特的特征。心脏Treg的积累主要是由于循环Treg池的招募，而局部增殖也有助于它们的扩张。此外，心脏Tregs中重复检测到的t细胞受体比脾脏Tregs中重复检测到的t细胞受体多，这表明了一种克隆扩增模型。此外，通过T细胞受体谱分析和常规CD4(+) T细胞过继性转移实验证实，Helios（高）Nrp-1（高）表型证明了心脏Tregs的主要胸腺起源，而常规CD4(+) T细胞的表型转化贡献较小。白细胞介素-33/抑制致瘤性2轴对维持心脏Treg种群至关重要。最后，我们证明了在心脏treg中高度表达的Sparc是通过增加胶原含量和促进梗死区成熟来保护心脏免受心肌梗死的关键因素。结论：我们鉴定并表征了一个表型和功能上独特的心脏treg群体，这可能为利用treg在心肌梗死和其他心脏疾病中的心脏保护作用奠定基础。
Background:Regulatory T cells (Tregs), traditionally recognized as potent suppressors of immune response, are increasingly attracting attention because of a second major function: residing in parenchymal tissues and maintaining local homeostasis. However, the existence, unique phenotype, and function of so-called tissue Tregs in the heart remain unclear.Methods:In mouse models of myocardial infarction (MI), myocardial ischemia/reperfusion injury, or cardiac cryoinjury, the dynamic accumulation of Tregs in the injured myocardium was monitored. The bulk RNA sequencing was performed to analyze the transcriptomic characteristics of Tregs from the injured myocardium after MI or ischemia/reperfusion injury. Photoconversion, parabiosis, single-cell T-cell receptor sequencing, and adoptive transfer were applied to determine the source of heart Tregs. The involvement of the interleukin-33/suppression of tumorigenicity 2 axis and Sparc (secreted acidic cysteine-rich glycoprotein), a molecule upregulated in heart Tregs, was further evaluated in functional assays.Results:We showed that Tregs were highly enriched in the myocardium of MI, ischemia/reperfusion injury, and cryoinjury mice. Transcriptomic data revealed that Tregs isolated from the injured hearts had plenty of differentially expressed transcripts in comparison with their lymphoid counterparts, including heart-draining lymphoid nodes, with a phenotype of promoting infarct repair, indicating a unique characteristic. The heart Tregs were accumulated mainly because of recruitment from the circulating Treg pool, whereas local proliferation also contributed to their expansion. Moreover, a remarkable case of repeatedly detected T-cell receptor of heart Tregs, more than that of spleen Tregs, suggests a model of clonal expansion. Besides, Helios(high)Nrp-1(high) phenotype proved the mainly thymic origin of heart Tregs, with a small contribution of phenotypic conversion of conventional CD4(+) T cells, proved by the analysis of T-cell receptor repertoires and conventional CD4(+) T cells adoptive transfer experiments. The interleukin-33/suppression of tumorigenicity 2 axis was essential for sustaining heart Treg populations. Last, we demonstrated that Sparc, which was highly expressed by heart Tregs, acted as a critical factor to protect the heart against MI by increasing collagen content and boosting maturation in the infarct zone.Conclusions:We identified and characterized a phenotypically and functionally unique population of heart Tregs that may lay the foundation to harness Tregs for cardioprotection in MI and other cardiac diseases.