Cytotoxic CD8+ T cells promote granzyme B-dependent adverse post-ischemic cardiac remodeling
Icía Santos‐Zas, Jérémie Lemarie, Ivana Zlatanova, Marine Cachanado, Jean-Christophe Seghezzi, Hakim Benamer, Pascal Goube, Marie Vandestienne, Raphael M. Cohen, Maya Ezzo, Vincent Duval, Yujiao Zhang, Jin Bo Su, Alain Bizé, Lucien Sambin, Philippe Bonnin, Maxime Branchereau, Christophe Heymes, Corinne Tanchot, José Vilar, Clément Delacroix, Jean‐Sébastien Hulot, Clément Cochain, Patrick Bruneval, Nicolas Danchin, Alain Tedgui, Ziad Mallat, Tabassome Simon, Bijan Ghaleh, Jean‐Sébastien Silvestre, Hafid Ait‐Oufella
Abstract
Abstract 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.