CD4+TEM cells drive the progression from acute myocarditis to dilated cardiomyopathy in CVB3-induced BALB/c mice

Abstract

Acute viral myocarditis can progress to chronic myocarditis leading to dilated cardiomyopathy (DCM). Persistent CD4⁺ T-cell-mediated autoimmunity triggered by infection plays a critical role in this progression. Increasing evidence demonstrates that effector memory CD4⁺T (CD4⁺T_EM) cells, a subset of memory CD4⁺ T cells, are crucial pathogenic mediators of many autoimmune diseases. However, the role of CD4⁺T_EM cells during the progression from acute viral myocarditis to DCM remains unknown. In this study, we observed an increase in CD4⁺T_EM cells both in the periphery and the heart, and memory CD4⁺ T cells were the predominant sources of IL-17A and IFN-γ among inflamed heart-infiltrating CD4⁺ T cells during the progression from acute myocarditis to chronic myocarditis and DCM in CVB3-induced BALB/c mice. Moreover, splenic CD4⁺T_EM cells sorted from DCM mice induced by CVB3 were found to respond to cardiac self-antigens ex vivo. Additionally, adoptive transfer experiments substantiated their pathogenic impact, inducing sustained myocardial inflammation, tissue fibrosis, cardiac injury, and impairment of cardiac systolic function in vivo. Our findings illustrate that long-lived CD4⁺T_EM cells are important contributors to the progression from acute viral myocarditis into DCM.

Keywords: Autoimmunity; Dilated cardiomyopathy; Effector memory CD4(+) T cell; Viral myocarditis.