CD8+T-cells negatively regulate inflammation post-myocardial infarction

Abstract

The adaptive immune response is key for cardiac wound healing post-myocardial infarction (MI) despite low T-cell numbers. We hypothesized that CD8+T-cells regulate the inflammatory response, leading to decreased survival and cardiac function post-MI. We performed permanent occlusion of the left anterior descending coronary artery on C57BL/6J and CD8atm1makmice (deficient in functional CD8+T-cells). CD8atm1makmice had increased survival at 7 days post-MI compared with that of the wild-type (WT) and improved cardiac physiology at day 7 post-MI. Despite having less mortality, 100% of the CD8atm1makgroup died because of cardiac rupture compared with only 33% of the WT. Picrosirius red staining and collagen immunoblotting indicated an acceleration of fibrosis in the infarct area as well as remote area in the CD8atm1makmice; however, this increase was due to elevated soluble collagen implicating poor scar formation. Plasma and tissue inflammation were exacerbated as indicated by higher levels of Cxcl1, Ccl11, matrix metalloproteinase (MMP)-2, and MMP-9. Immunohistochemistry and flow cytometry indicated that the CD8atm1makgroup had augmented numbers of neutrophils and macrophages at post-MI day 3 and increased mast cell markers at post-MI day 7. Cleavage of tyrosine-protein kinase MER was increased in the CD8atm1makmice, resulting in delayed removal of necrotic tissue. In conclusion, despite having improved cardiac physiology and overall survival, CD8atm1makmice had increased innate inflammation and poor scar formation, leading to higher incidence of cardiac rupture. Our data suggest that the role of CD8+T-cells in post-MI recovery may be both beneficial and detrimental to cardiac remodeling and is mediated via a cell-specific mechanism.NEW & NOTEWORTHY We identified new mechanisms implicating CD8+T-cells as regulators of the post-myocardial infarction (MI) wound healing process. Mice without functional CD8+T-cells had improved cardiac physiology and less mortality 7 days post MI compared with wild-type animals. Despite having better overall survival, animals lacking functional CD8+T-cells had delayed removal of necrotic tissue, leading to poor scar formation and increased cardiac rupture, suggesting that CD8+T-cells play a dual role in the cardiac remodeling process.