A cute myocardial ischemia induces an intense activation of the immune system leading to cytokines and chemokines production 1,2 and to the recruitment of neutrophils and mononuclear cells in the infarcted area.3,4 Early proinflammatory signals are crucial in mediating the response to injury, regulating clearance of dead cardiac myocytes and initiating the cellular events necessary for wound healing. However, optimal healing requires activation of inhibitory mechanisms that suppress cytokine and chemokine synthesis and mediate resolution of the inflammatory infiltrate. Therefore, limiting the inflammatory response amplification seems to be important for containment of injury and optimal infarct healing. Triggering receptor expressed on myeloid cells-1 (TREM-1) is an immune-receptor expressed by neutrophils, macrophages, and mature monocytes that acts as an amplifier of the innate immune response.6 It has been shown that blockade of TREM-1 activation by short inhibitory peptides or fusion protein protected from hyper-responsiveness and death in various models of severe infections.

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.