Cytotoxic CD8+ T cells promote granzyme B-dependent adverse post-ischemic cardiac remodeling

Acute myocardial infarction is a common condition responsible for heart failure and sudden death. Here, we show that following acute myocardial infarction in mice, CD8(+) T lymphocytes are recruited and activated in the ischemic heart tissue and release Granzyme B, leading to cardiomyocyte apoptosis, adverse ventricular remodeling and deterioration of myocardial function. Depletion of CD8(+) T lymphocytes decreases apoptosis within the ischemic myocardium, hampers inflammatory response, limits myocardial injury and improves heart function. These effects are recapitulated in mice with Granzyme B-deficient CD8(+) T cells. The protective effect of CD8 depletion on heart function is confirmed by using a model of ischemia/reperfusion in pigs. Finally, we reveal that elevated circulating levels of GRANZYME B in patients with acute myocardial infarction predict increased risk of death at 1-year follow-up. Our work unravels a deleterious role of CD8(+) T lymphocytes following acute ischemia, and suggests potential therapeutic strategies targeting pathogenic CD8(+) T lymphocytes in the setting of acute myocardial infarction. Immune cells contribute to adverse remodeling following myocardial infarction. Here the authors show in mice and pigs that CD8(+) lymphocytes release Granzyme B in the infarcted heart leading to cardiomyocyte death, enhanced inflammation and deterioration of cardiac function.

Automated summary

This study reveals the detrimental role of CD8(+) T lymphocytes following acute myocardial infarction, showing that they release Granzyme B in the ischemic heart tissue leading to cardiomyocyte apoptosis, adverse ventricular remodeling, and deterioration of myocardial function. Depletion of CD8(+) T lymphocytes leads to reduced apoptosis, inhibited inflammatory response, limited myocardial injury, and improved heart function. Elevated circulating levels of GRANZYME B in AMI patients may predict increased risk of death at 1-year follow-up. Targeting pathogenic CD8(+) T lymphocytes could be a potential therapeutic strategy in the setting of acute myocardial infarction.