Susceptibility to myocarditis is dependent on the response of αβ T lymphocytes to coxsackieviral infection

Abstract

Viral myocarditis is an important cause of heart failure and dilated cardiomyopathy. T lymphocytes are implicated in myocardial damage in murine models of coxsackievirus B3 (CVB3) myocarditis. We used knockout mice lacking CD4 (CD4(-/-)), CD8 (CD8(-/-)), both coreceptors (CD4(-/-)CD8(-/-)), or the T-cell receptor β chain (TCRβ(-/-)) to address the contribution of T-cell subpopulations to host susceptibility to CVB3 myocarditis. Severity of disease was magnified in CD8(-/-) mice but attenuated in CD4(-/-) mice, consistent with a pathogenic role for CD4+ lymphocytes. Elimination of both CD4 and CD8 molecules from T lymphocytes by genetic knockout better protected mice from myocarditis, demonstrating that both CD4+ and CD8+ T cells contribute to host susceptibility. The same benefit occurred in TCRβ(-/-) mice, with prolonged survival and minimal myocardial disease observed after CVB3 infection. Elevated interferon-γ and decreased tumor necrosis factor-α expression are associated with attenuated myocardial damage in CD4(-/-)CD8(- /-) mice. These results show that the presence of TCRαβ+ T cells enhances host susceptibility to myocarditis. The severity of myocardial damage and associated mortality are dependent on the predominant T-cell type available to respond to CVB3 infection. One mechanism by which CD4+ and CD8+ T-cell subsets influence the pathogenesis of myocarditis may involve specific cytokine expression patterns.