A Unique Population of Regulatory T Cells in Heart Potentiates Cardiac Protection From Myocardial Infarction

Abstract

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 (I/R 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 I/R injury. Photoconversion, parabiosis, single-cell TCR sequencing and adoptive transfer were applied to determine the source of heart Tregs. The involvement of the interleukin (IL)-33/ST2 axis and secreted acidic cysteine rich glycoprotein (Sparc), 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, I/R injury and cryoinjury mice. Transcriptomic data revealed that Tregs isolated from the injured hearts had plenty of differentially expressed transcripts compared to 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 due to recruitment from circulating Treg pool, while local proliferation also contributed to their expansion. Moreover, a remarkable case of repeatedly detected TCR 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 (Tconvs), proved by the analysis of TCR repertoires and Tconvs adoptive transfer experiments. Notably, the IL-33/ST2 axis was essential for sustaining heart Treg populations. Finally, 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, which may lay the foundation to harness Tregs for cardioprotection in MI and other cardiac diseases.

Reprogramming adult tendon healing using regenerative neonatal regulatory T cells

“…Among regeneration-competent adult tissues, (e.g., muscle, lung, skin), release of alarmins following injury stimulates secretion of the EGFR-ligand amphiregulin by Tregs that is critical for tissue repair 19,21,23 . In contrast, adult Tregs are not sufficient to promote regeneration in non-regenerative tissues (e.g., adult heart, brain) despite recruitment and activation [42][43][44] . While impaired regeneration may be due in part to limited stem/progenitor cell pools, recent studies suggest inflammatory dysregulation also contributes to non-regenerative healing 45,46 .…”

Regulatory T Cells in Chronic Heart Failure

“…More importantly, single-cell sequencing helps us to map the development trajectories of cells by in-depth analysis of the transcriptome characteristics of single cells. The characteristics of individual Tregs had been described in atherosclerosis, myocarditis, MI, and pressure overload-induced HF in mice ( 4 , 5 , 20 , 135 ). We also reported the differences in transcriptome characteristics between heart Tregs and splenic Tregs after MI and described an oligoclonal feature of heart Tregs ( 20 ).…”

“…The characteristics of individual Tregs had been described in atherosclerosis, myocarditis, MI, and pressure overload-induced HF in mice ( 4 , 5 , 20 , 135 ). We also reported the differences in transcriptome characteristics between heart Tregs and splenic Tregs after MI and described an oligoclonal feature of heart Tregs ( 20 ). All the results assisted us to identify the subset of Tregs that is beneficial in tissue repair or prognosis of HF.…”

“…It indicates an enhanced inhibitory capacity of heart Tregs. These results may indicate a different function of tissue Tregs and lymphoid Tregs ( 20 , 97 ). In a previous study, we also showed that Tregs inhibited the response of cytotoxic CD8 + T cells in mice after MI ( 22 ).…”

“…Recently, we reported a kind of Tregs that expresses “secreted protein acidic and rich in cysteine” (SPARC) in the hearts of MI mice. They played a protective role in preventing cardiac rupture ( 20 ). This result demonstrates that heart Tregs participate in cardiac repair directly.…”