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.

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Recently, the roles of toll like receptor (TLR) gene polymorphisms in atherosclerotic diseases were extensively investigated, with conflicting results. Therefore, we performed this study to better assess the relationship between TLR gene variants and atherosclerosis. Eligible studies were searched in PubMed, MEDLINE, EMBASE, Web of Science and CNKI. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate associations between TLR gene polymorphisms and atherosclerosis. A total of 40 studies covering 19,657 cases and 15,660 controls were finally included in our systematic review and meta-analysis. Significant correlations with atherosclerosis susceptibility were found for the TLR1 rs5743551 polymorphism (dominant model: 95% CI 1.03-1.79; recessive model: 95% CI 0.28-0.97; allele model: 95% CI 1.07-1.69), TLR1 rs5743611 polymorphism (dominant model: 95% CI 0.56-0.98) and TLR6 rs5743810 polymorphism (recessive model: 95% CI 0.56-0.92) in overall analyses. Moreover, further subgroup analyses revealed that TLR4 rs1927911 polymorphism was significantly associated with the risk of cerebral infarction in the recessive model (95% CI 0.46-0.96), whereas TLR4 rs4986791 polymorphism was significantly correlated with susceptibility to atherosclerosis among Asians in the dominant (95% CI 1.58-6.66), additive (95% CI 0.13-0.69) and allele (95% CI 1.58-5.53) models. However, no positive results were found for the other 13 TLR polymorphisms. In conclusion, our findings indicate that most TLR gene polymorphisms may not be implicated in the pathogenesis of atherosclerosis, whereas certain TLR gene variations, such as rs5743551, rs5743611, rs5743810, rs4986791 and rs1927911, may serve as genetic biomarkers of atherosclerotic diseases.

This systematic review and meta-analysis aimed to better elucidate the roles of genetic factors in Kawasaki disease (KD), and determine the potential genetic biomarkers of KD. The systematic literature search of PubMed, Medline, Embase, Web of Science and CNKI identified 164 eligible studies. The qualitative synthesis revealed that 62 genes may be correlated with the susceptibility to KD, and 47 genes may be associated with the incidence of coronary artery lesions (CALs) in KD. A total of 53 polymorphisms in 34 genes were investigated in further quantitative synthesis. Of these, 23 gene polymorphisms were found to be significantly correlated with KD susceptibility, and 10 gene polymorphisms were found to be significantly associated with the incidence of CALs in KD. In conclusion, our findings indicate that gene polymorphisms of ACE, BLK, CASP3, CD40, FCGR2A, FGβ, HLA-E, IL1A, IL6, ITPKC, LTA, MPO, PD1, SMAD3, CCL17 and TNF may affect KD susceptibility. Besides, genetic variations in BTNL2, CASP3, FCGR2A, FGF23, FGβ, GRIN3A, HLA-E, IL10, ITPKC and TGFBR2 may serve as biomarkers of CALs in KD.