Role of CD1d in Coxsackievirus B3-induced myocarditis

The myocarditic (W) variant of Coxsacldevirus B3 (CVB3) causes severe myocarditis in BALB/c mice and BALB/c mice lacking the invariant Jalpha281 gene, but minimal disease in BALB/c CD1d(-/-) animals. This indicates that CD1d expression is important in this disease but does not involve the invariant NKT cell often associated with CD1d-restricted immunity. The H3 variant of the virus increases CD1d expression in vitro in neonatal cardiac myocytes whereas a nonmyocarditic (H310A1) variant does not. Vgamma4(+) T cells show increased activation in both H3-infected BALB/c and Jalpha218(-/-) mice compared with CD1d(-/-) animals. The activated BALB/c Vgamma4(+) T cells from H3-infected mice kill H3-infected BALB/c myocytes and cytotoxicity is blocked with anti-CD1d but not with anti-MHC class I (K-d/D-d) or class II (IA/IE) mAbs. In contrast, H3 virus-infected CD1d(-/-) myocytes are not killed. These studies demonstrate that CD1d expression is essential for pathogenicity of CVB3-induced myocarditis, that CD1d expression is increased early after infection in vivo in CD1d(+) mice infected with the myocarditic but not with the nonmyocarditic CVB3 variant, and that Vgamma4(+) T cells, which are known to promote myocarditis susceptibility, appear to recognize CD1d expressed by CVB3-infected myocytes.