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Journal of Virology, March 2005, p. 2659-2665, Vol. 79, No. 5
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.5.2659-2665.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Department of Pathology, University of Vermont, Burlington, Vermont

Received 6 April 2004/ Accepted 5 September 2004

Giving C57BL/6 mice 10⁴ PFU of coxsackievirus B3 (H3 variant) fails to induce myocarditis, but increasing the initial virus inoculum to 10⁵ or 10⁶ PFU 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 10⁴ PFU were reduced. Tumor necrosis factor alpha (TNF-) concentrations in the heart were increased in all infected mice, but cytokine levels were highest in mice given the larger virus inocula. TNF-^–/– 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 V4⁺ cells. Cardiac endothelial cells isolated from C57BL/6 and p75 TNFR^–/– mice upregulate CD1d, the molecule recognized by V4⁺ 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-, failed to elicit CD1d expression, but TNF- treatment of H310A1-infected endothelial cells increased CD1d levels to those seen in H3-infected cells. TNF- treatment of uninfected endothelial cells had only a modest effect on CD1d expression, suggesting that optimal CD1d upregulation requires both infection and TNF- signaling.

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