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

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.

SUBMITTER: Santos-Zas I

PROVIDER: S-EPMC7935973 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Santos-Zas Icia I Lemarié Jeremie J Zlatanova Ivana I Cachanado Marine M Seghezzi Jean-Christophe JC Benamer Hakim H Goube Pascal P Vandestienne Marie M Cohen Raphael R Ezzo Maya M Duval Vincent V Zhang Yujiao Y Su Jin-Bo JB Bizé Alain A Sambin Lucien L Bonnin Philippe P Branchereau Maxime M Heymes Christophe C Tanchot Corinne C Vilar José J Delacroix Clement C Hulot Jean-Sebastien JS Cochain Clement C Bruneval Patrick P Danchin Nicolas N Tedgui Alain A Mallat Ziad Z Simon Tabassome T Ghaleh Bijan B Silvestre Jean-Sébastien JS Ait-Oufella Hafid H

Nature communications 20210305 1

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 ...[more]

PMID: 33674611

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Project description:Background: Guided by long-term safety data for AAV5 in humans, our translational study investigated whether AAV5 effectively delivers genes to healthy and achieve therapeutic efficacy in dysfunctional human-sized hearts, using a clinically applicable mode of administration and vector dosages. Methods & Results: In a first biodistribution study, AAV5 (11013 vector genomes; vgs) - carrying the reporter gene luciferase (luc) - achieved broad and homogenous transduction of the left ventricle (LV) of healthy German farm pigs 30 days after percutaneous catheter-based retrograde intravenous delivery (CRID), as measured by vector genome and luc mRNA assessments. Both its myocardial and extra-cardiac distribution patterns were advantageous compared to AAV9-luc and AAV6-luc. Using the cardioprotective human gene S100A1 (hS100A1) in a subsequent therapy study, effective myocardial transduction with AAV5-hS100A1 (11013 vgcs) by CRID prevented LV myocardial infarction (MI) enlargement and improved systolic contractile performance after 3 months in a porcine model with chronic post-MI cardiac dysfunction, as assessed by serial cardiac magnetic resonance imaging. The use of a cardiac-biased promoter ensured cardiac-targeted hS100A1 expression without signs of clinical toxicity, as shown by RT-PCR analysis, clinical chemistry and blood count. A previously unknown anti-inflammatory effect of hS100A1 in damaged myocardium, detected and linked to the therapeutic actions by a cardiac transcriptome weighted gene coexpression network analysis, was confirmed using AAV5-hS100A1 therapy in a post-MI mouse model, as measured by RT-PCR and echocardiography. Conclusion: Providing the clinically relevant proof-of-concept for AAV5 to effectively transduce healthy and dysfunctional human-sized hearts, its clinical long-term safety, scalable producibility as well as low pre-existing immunity in humans may predestine AAV5 as an effective and safe gene carrier for a prevalent disease as chronic heart failure, using therapeutic genetic effectors, such as hS100A1 or others.

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

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Cytotoxic CD8<sup>+</sup> T cells promote granzyme B-dependent adverse post-ischemic cardiac remodeling.

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

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Cytotoxic CD8&lt;sup&gt;+&lt;/sup&gt; T cells promote granzyme B-dependent adverse post-ischemic cardiac remodeling.

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

Cytotoxic CD8<sup>+</sup> T cells promote granzyme B-dependent adverse post-ischemic cardiac remodeling.