CD8+ T-cells negatively regulate inflammation post-myocardial infarction.
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 CD8a mice (deficient in functional CD8+ T-cells). CD8a mice 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 CD8a group 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 CD8a mice; 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 CD8a group 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 CD8a mice, resulting in delayed removal of necrotic tissue. In conclusion, despite having improved cardiac physiology and overall survival, CD8a mice 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.
['Ilatovskaya|Daria V|DV|', 'Pitts|Cooper|C|', 'Clayton|Joshua|J|', 'Domondon|Mark|M|', 'Troncoso|Miguel|M|', 'Pippin|Sarah|S|', 'DeLeon-Pennell|Kristine Y|KY|0000-0002-9647-6112']
D000818:Animals D016827:CD8 Antigens D018414:CD8-Positive T-Lymphocytes D003094:Collagen D004195:Disease Models, Animal D005260:Female D005355:Fibrosis D006342:Heart Rupture, Post-Infarction D007113:Immunity, Innate D007249:Inflammation D018836:Inflammation Mediators D008297:Male D008810:Mice, Inbred C57BL D008817:Mice, Mutant Strains D009154:Mutation D009203:Myocardial Infarction D009206:Myocardium D015398:Signal Transduction D020257:Ventricular Remodeling
T-cell inflammation wound healing myocardial infarction