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

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

doi:10.1038/s41467-021-21737-9

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.

Highlights

Acute myocardial infarction is a common condition responsible for heart failure and sudden death
We found that CD3+CD8+ T (Fig. 1A–C) and CD3+CD4+ T lymphocytes accumulated in the injured myocardium as early as day 1 and peaked at day 3 after myocardial infarction (MI)
Flow cytometry analyses showed that the proportion of CD8+ T cells expressing CD69 and CD107a increased during the first week after MI in the heart (Fig. 1F), as well as in the draining mediastinal lymph nodes (Supplementary Fig. 5)

Summary

Introduction

Acute myocardial infarction is a common condition responsible for heart failure and sudden death. 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. We showed that, following acute MI in mice, CD8+ T lymphocytes are recruited in the ischemic heart and foster cardiomyocyte death through the local release of Granzyme B, leading to enhanced myocardial inflammation, tissue injury, and deterioration of myocardial function. We unraveled that immunotherapy based on the administration of neutralizing antibody directed against CD8+ T cells promotes cardiac repair in a mouse model of MI as well as in a pig model of cardiac ischemia-reperfusion

Methods

Results

Conclusion