Susceptibility to myocarditis is dependent on the response of alpha beta Tlymphocytes to coxsackieviral infection

Viral myocarditis is an important cause of heart failure and dilated cardio myopathy. T lymphocytes are implicated in myocardial damage in murine model s of coxsackievirus B3 (CVB3) myocarditis. We used knockout mice lacking CD 4 (CD4(-/-)), CD8 (CD8(-/-)), both coreceptors (CD4(-/-)CD8(-/-)), or the T -cell receptor beta chain (TCR beta(-/-)) 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, co nsistent with a pathogenic role for CD4(+) lymphocytes. Elimination of both CD4 and CD8 molecules from T lymphocytes by genetic knockout better protec ted mice from myocarditis, demonstrating that both CD4(+) and CD8(+) T cell s contribute to host susceptibility. The same benefit occurred in TCR beta( -/-) mice, with prolonged survival and minimal myocardial disease observed after CVB3 infection. Elevated interferon-gamma and decreased tumor necrosi s factor-a expression are associated with attenuated myocardial damage in C D4(-/-)CD8(-/-) mice. These results show that the presence of TCR alpha bet a(+) T cells enhances host susceptibility to myocarditis. The severity of m yocardial 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.