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

被引：137

作者：

Santos-Zas, Icia ^{[1
]}

Lemarie, Jeremie ^{[1
]}

Zlatanova, Ivana ^{[1
]}

Cachanado, Marine ^{[2
,3
]}

Seghezzi, Jean-Christophe ^{[4
]}

Benamer, Hakim ^{[5
]}

Goube, Pascal ^{[6
]}

Vandestienne, Marie ^{[1
]}

Cohen, Raphael ^{[1
]}

Ezzo, Maya ^{[1
]}

Duval, Vincent ^{[1
]}

Zhang, Yujiao ^{[1
]}

Su, Jin-Bo ^{[7
]}

Bize, Alain ^{[7
]}

Sambin, Lucien ^{[7
]}

Bonnin, Philippe ^{[8
]}

Branchereau, Maxime ^{[9
]}

Heymes, Christophe ^{[9
]}

Tanchot, Corinne ^{[1
]}

Vilar, Jose ^{[1
]}

Delacroix, Clement ^{[1
]}

Hulot, Jean-Sebastien ^{[1
]}

Cochain, Clement ^{[10
]}

Bruneval, Patrick ^{[1
,11
]}

Danchin, Nicolas ^{[12
]}

Tedgui, Alain ^{[1
]}

Mallat, Ziad ^{[1
,13
]}

Simon, Tabassome ^{[2
,3
,14
,15
,16
]}

Ghaleh, Bijan ^{[7
]}

Silvestre, Jean-Sebastien ^{[1
]}

Ait-Oufella, Hafid ^{[1
,17
]}

机构：

[1] Univ Paris, INSERM, PARCC, F-75015 Paris, France

[2] Hop St Antoine, AP HP, APHP SU, Paris, France

[3] Hop St Antoine, Dept Clin Pharmacol & Clin Res Platform URCEST CR, Paris, France

[4] Ctr Hosp Compiegne, Serv Cardiol, Compiegne, France

[5] Inst Cardiovasc Paris Sud, Serv Cardiol, Paris, France

[6] Ctr Hosp Corbeil, Serv Cardiol, Corbeil Essonnes, France

[7] Ecole Natl Vet Alfort, UPEC, Equipe 03, Inserm U955 IMRB, Maisons Alfort, France

[8] Hop Lariboisiere, AP HP, Dept Physiol, Inserm U965, Paris, France

[9] Univ Paul Sabatier, Inserm U1048, Inst Malad Metab & Cardiovasc I2MC, Toulouse, France

[10] Univ Hosp Wurzburg, Inst Expt Biomed, Wurzburg, Germany

[11] Hop Europeen Georges Pompidou, AP HP, Serv Anatomopathol, Paris, France

[12] Hop Europeen Georges Pompidou, AP HP, Serv Cardiol, Paris, France

[13] Univ Cambridge, Addenbrookes Hosp, Div Cardiovasc Med, Cambridge CB2 2QQ, England

[14] Sorbonne Univ, UPMC Site St Antoine, APHP SU, AP HP,Serv Pharmacol, Paris, France

[15] Sorbonne Univ, Dept Clin Pharmacol, Paris, France

[16] Sorbonne Univ, Hop St Antoine, Clin Res Platform URCEST CRB CRC EST, Paris, France

[17] Sorbonne Univ, Serv Med Intens Reanimat, AP HP, Paris, France

来源：

NATURE COMMUNICATIONS | 2021年 / 12卷 / 01期

关键词：

LYMPHOPENIA-INDUCED PROLIFERATION; MYOCARDIAL-INFARCTION; ST-ELEVATION; HEART; LYMPHOCYTES; INJURY; ACTIVATION; DETERMINANTS; MANAGEMENT; PERFORIN;

D O I：

10.1038/s41467-021-21737-9

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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. Immune cells contribute to adverse remodeling following myocardial infarction. Here the authors show in mice and pigs that CD8(+) lymphocytes release Granzyme B in the infarcted heart leading to cardiomyocyte death, enhanced inflammation and deterioration of cardiac function.

引用

页数：13

共 43 条

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