Innate immunity promotes both the generation of autoimmunity and immunoregulation of adaptive immunity. Transgenic mice expressing the tumor necrosis factor-alpha (TNF-alpha) gene under the cardiac myosin promoter (TNF1.6 mice) develop dilated cardiomyopathy. Transgenic mice show extensive cardiac inflammation, suggesting that immunopathogenic mechanisms may promote cardiomyopathy. Two coxsackievirus B3 (CVB3) variants infect and replicate in the heart. H3 variant is highly myocarditic, but H310A1 variant activates CD4(+) T regulatory cells, which protect against viral myocarditis. T-cell depletion of TNF1.6 mice using monoclonal anti-CD3 or anti-CD4 antibody significantly reduced heart size and plasma troponin I concentrations compared with control TNF1.6 mice. Cardiomyopathy in TNF1.6 mice correlates to a CD4(+)Th1 response and autoimmune IgG2a antibodies. TNF1.6 mice infected with H310A1 virus reduced heart size and cardiac inflammation corresponding to the activation of CD4(+)CD25(+)FoxP3(+) (T regulatory cells). Immunosuppression is dependent on IL-10 but not TGFbeta. Adoptive transfer of the CD4(+)CD25(+) cells from H310A1-infected mice into uninfected TNF1.6 recipients abrogated cardiomyopathy. Exogenous administration of recombinant TNF-alpha to H310A1-infected mice for 4 days abrogated immunosuppression. Cardiac enlargement in TNF1.6 mice is partly attributable to T-cell activation and humoral autoimmunity caused by cytokine expression. T regulatory cells induced by H310A1 virus abrogate autoimmunity caused by TNF-alpha overexpression. H3 virus infection induces high levels of systemic TNF-alpha, whereas H310A1 virus does not. The low TNF-alpha response during H310A1 infections is likely responsible for the T regulatory cell response in these animals.