Identification of noncytotoxic and IL-10-producing CD8+AT2R+ T cell population in response to ischemic heart injury.

Emerging evidence suggests a cardioprotective role of the angiotensin AT2R, albeit the underlying cellular mechanisms are not well understood. We aimed in this article to elucidate a potential role of cardiac angiotensin AT2R in regulating cellular immune response to ischemic heart injury. Seven days after myocardial infarction in rats, double-immunofluorescence staining showed that AT2R was detected in a fraction of CD8 + T cells infiltrating in the peri-infarct myocardium. We developed a method that allowed the isolation of myocardial infiltrating CD8 + AT2R + T cells using modified MACS, and further characterization and purification with flow cytometry. Although the CD8 + AT2R − T cells exhibited potent cytotoxicity to both adult and fetal cardiomyocytes (CMs), the CD8 + AT2R + T cells were noncytotoxic to these CMs. The CD8 + AT2R + T cells were characterized by upregulated IL-10 and downregulated IL-2 and INF-γ expression when compared with CD8 + AT2R − T cells. We further showed that IL-10 gene expression was enhanced in CD8 + T cells on in vitro AT2R stimulation. Importantly, in vivo AT2R activation engendered an increment of CD8 + AT2R + T cells and IL-10 production in the ischemic myocardium. In addition, intramyocardial transplantation of CD8 + AT2R + T cells (versus CD8 + AT2R − ) led to reduced ischemic heart injury. Moreover, the CD8 + AT2R + T cell population was also demonstrated in human peripheral blood. Thus, we have defined the cardioprotective CD8 + AT2R + T cell population, which increases during ischemic heart injury and contributes to maintaining CM viability and providing IL-10, hence revealing an AT2R-mediated cellular mechanism in modulating adaptive immune response in the heart.