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

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.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.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, HelioshighNrp-1high 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.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.