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(Circulation Research. 2006;99:1109.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Coxsackievirus B3 Induces T Regulatory Cells, Which Inhibit Cardiomyopathy in Tumor Necrosis Factor- Transgenic Mice

Sally A. Huber, Arthur M. Feldman, Danielle Sartini

From the Department of Pathology (S.A.H., D.S.), University of Vermont, Colchester; and Department of Medicine (A.M.F.), Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pa.

Correspondence to Dr Sally Huber, Department of Pathology, University of Vermont, 208 South Park Dr, Ste 2, Colchester, VT 05446. E-mail Sally.Huber{at}uvm.edu

Innate immunity promotes both the generation of autoimmunity and immunoregulation of adaptive immunity. Transgenic mice expressing the tumor necrosis factor- (TNF-) 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 TGFß. Adoptive transfer of the CD4⁺CD25⁺ cells from H310A1-infected mice into uninfected TNF1.6 recipients abrogated cardiomyopathy. Exogenous administration of recombinant TNF- 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- overexpression. H3 virus infection induces high levels of systemic TNF-, whereas H310A1 virus does not. The low TNF- response during H310A1 infections is likely responsible for the T regulatory cell response in these animals.

Key Words: myocarditis • inflammation • infection

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