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

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Santos-Zas, Icía | Lemarié, Jérémie | Zlatanova, Ivana | Cachanado, Marine | Seghezzi, Jean-Christophe | Benamer, Hakim | Goube, Pascal | Vandestienne, Marie | Cohen, Raphael | Ezzo, Maya | Duval, Vincent | Zhang, Yujiao | Su, Jin-Bo | Bizé, Alain | Sambin, Lucien | Bonnin, Philippe | Branchereau, Maxime | Heymes, Christophe | Tanchot, Corinne | Vilar, José | Delacroix, Clement | Hulot, Jean-Sebastien | Cochain, Clement | Bruneval, Patrick | Danchin, Nicolas | Tedgui, Alain | Mallat, Ziad | Simon, Tabassome | Ghaleh, Bijan | Silvestre, Jean-Sébastien | Ait-Oufella, Hafid

Edité par CCSD ; Nature Publishing Group -

International audience. 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.

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