Roles of Tumor Necrosis Factor Alpha (TNF-α) and the p55 TNF Receptor in CD1d Induction and Coxsackievirus B3-Induced Myocarditis

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Abstract
Giving C57BL/6 mice 104PFU of coxsackievirus B3 (H3 variant) fails to induce myocarditis, but increasing the initial virus inoculum to 105or 106PFU causes significant cardiac disease. Virus titers in the heart were equivalent at days 3 and 7 in mice given all three virus doses, but day 3 titers in the pancreases of mice inoculated with 104PFU were reduced. Tumor necrosis factor alpha (TNF-α) concentrations in the heart were increased in all infected mice, but cytokine levels were highest in mice given the larger virus inocula. TNF-α−/−and p55 TNF receptor-negative (TNFR−/−) mice developed minimal myocarditis compared to B6;129 or C57BL/6 control mice. p75 TNFR−/−mice were as disease susceptible as C57BL/6 animals. No significant differences in virus titers in heart or pancreas were observed between the groups, but C57BL/6 and p75 TNFR−/−animals showed 10-fold more inflammatory cells in the heart than p55 TNFR−/−mice, and the cell population was comprised of high concentrations of CD4+gamma interferon-positive and Vγ4+cells. Cardiac endothelial cells isolated from C57BL/6 and p75 TNFR−/−mice upregulate CD1d, the molecule recognized by Vγ4+cells, but infection of TNF−/−or p55 TNFR−/−endothelial cells failed to upregulate CD1d. Infection of C57BL/6 endothelial cells with a nonmyocarditic coxsackievirus B3 variant, H310A1, which is a poor inducer of TNF-α, failed to elicit CD1d expression, but TNF-α treatment of H310A1-infected endothelial cells increased CD1d levels to those seen in H3-infected cells. TNF-α treatment of uninfected endothelial cells had only a modest effect on CD1d expression, suggesting that optimal CD1d upregulation requires both infection and TNF-α signaling.

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