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

Icía Santos-Zas (1) , Jérémie Lemarié (1) , Ivana Zlatanova (1) , Marine Cachanado (2) , Jean-Christophe Seghezzi (3) , Hakim Benamer (4) , Pascal Goube (5) , Marie Vandestienne (1) , Raphael Cohen (1) , Maya Ezzo (1) , Vincent Duval (1) , Yujiao Zhang (1) , Jin-Bo Su (6) , Alain Bizé (6) , Lucien Sambin (6) , Philippe Bonnin (7) , Maxime Branchereau (8) , Christophe Heymes (8) , Corinne Tanchot (1) , José Vilar (1) , Clement Delacroix (1) , Jean-Sebastien Hulot (1) , Clement Cochain (9) , Patrick Bruneval (1, 10) , Nicolas Danchin (10) , Alain Tedgui (1) , Ziad Mallat (1, 11) , Tabassome Simon (2) , Bijan Ghaleh (6) , Jean-Sébastien Silvestre (1) , Hafid Ait-Oufella (1, 2)

1 PARCC (UMR_S 970/ U970) - Paris-Centre de Recherche Cardiovasculaire
2 CHU Saint-Antoine [AP-HP]
3 CHCN - Centre Hospitalier Compiègne-Noyon
4 ICPS - Institut Cardiovasculaire Paris Sud
5 CH Sud Francilien - Centre Hospitalier Sud Francilien [Corbeil-Essonnes]
6 IMRB - Institut Mondor de Recherche Biomédicale
7 Institut des Vaisseaux et du Sang
8 I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
9 JMU - Julius-Maximilians-Universität Würzburg
10 HEGP - Hôpital Européen Georges Pompidou [APHP]
11 CAM - University of Cambridge [UK]

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.

Mots clés: Heart failure; Lymphocytes

Domaines: Médecine humaine et pathologie

Icía Santos-Zas, Jérémie Lemarié, Ivana Zlatanova, Marine Cachanado, Jean-Christophe Seghezzi, et al.. Cytotoxic CD8+ T cells promote granzyme B-dependent adverse post-ischemic cardiac remodeling. Nature Communications, 2021, 12 (1), ⟨10.1038/s41467-021-21737-9⟩. ⟨hal-03176357⟩