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

Icia Santos-Zas, Jeremie Lemarié, Ivana Zlatanova, Marine Cachanado, Jean-Christophe Seghezzi, Hakim Benamer, Pascal Goube, Marie Vandestienne, Raphael Cohen, Maya Ezzo, Vincent Duval, Yujiao Zhang, Jin-Bo Su, Alain Bizé, Lucien Sambin, Philippe Bonnin, Maxime Branchereau, Christophe Heymes, Corinne Tanchot, José Vilar, Clement Delacroix, Jean-Sebastien Hulot, Clement Cochain, Patrick Bruneval, Nicolas Danchin, Alain Tedgui, Ziad Mallat, Tabassome Simon, Bijan Ghaleh, Jean-Sébastien Silvestre and Hafid Ait-Oufella ()
Additional contact information
Icia Santos-Zas: Université de Paris, PARCC, INSERM
Jeremie Lemarié: Université de Paris, PARCC, INSERM
Ivana Zlatanova: Université de Paris, PARCC, INSERM
Marine Cachanado: Assistance Publique-Hôpitaux de Paris, APHP.SU; Department of Clinical Pharmacology and Clinical Research Platform (URCEST-CRB-CRC-EST), Hôpital Saint Antoine
Jean-Christophe Seghezzi: Service de cardiologie, Centre Hospitalier de Compiegne
Hakim Benamer: Service de cardiologie, Institut Cardiovasculaire Paris Sud
Pascal Goube: Service de cardiologie, Centre Hospitalier de Corbeil
Marie Vandestienne: Université de Paris, PARCC, INSERM
Raphael Cohen: Université de Paris, PARCC, INSERM
Maya Ezzo: Université de Paris, PARCC, INSERM
Vincent Duval: Université de Paris, PARCC, INSERM
Yujiao Zhang: Université de Paris, PARCC, INSERM
Jin-Bo Su: Inserm U955-IMRB, Equipe 03, UPEC, Ecole Nationale Vétérinaire d’Alfort
Alain Bizé: Inserm U955-IMRB, Equipe 03, UPEC, Ecole Nationale Vétérinaire d’Alfort
Lucien Sambin: Inserm U955-IMRB, Equipe 03, UPEC, Ecole Nationale Vétérinaire d’Alfort
Philippe Bonnin: Inserm U965, Department of Physiology, Assistance Publique Hôpitaux de Paris
Maxime Branchereau: Inserm U1048-Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), université Paul Sabatier
Christophe Heymes: Inserm U1048-Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), université Paul Sabatier
Corinne Tanchot: Université de Paris, PARCC, INSERM
José Vilar: Université de Paris, PARCC, INSERM
Clement Delacroix: Université de Paris, PARCC, INSERM
Jean-Sebastien Hulot: Université de Paris, PARCC, INSERM
Clement Cochain: Institute of Experimental Biomedicine, University Hospital Würzburg
Patrick Bruneval: Université de Paris, PARCC, INSERM
Nicolas Danchin: Service de cardiologie, Hôpital Europeen G. Pompidou, Assistance Publique, Hôpitaux de Paris
Alain Tedgui: Université de Paris, PARCC, INSERM
Ziad Mallat: Université de Paris, PARCC, INSERM
Tabassome Simon: Assistance Publique-Hôpitaux de Paris, APHP.SU; Department of Clinical Pharmacology and Clinical Research Platform (URCEST-CRB-CRC-EST), Hôpital Saint Antoine
Bijan Ghaleh: Inserm U955-IMRB, Equipe 03, UPEC, Ecole Nationale Vétérinaire d’Alfort
Jean-Sébastien Silvestre: Université de Paris, PARCC, INSERM
Hafid Ait-Oufella: Université de Paris, PARCC, INSERM

Nature Communications, 2021, vol. 12, issue 1, 1-13

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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21737-9

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DOI: 10.1038/s41467-021-21737-9

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