C57BL/6 mice develop a virus-specific cytotoxic T-lymphocyte (CTL) response after intraperitoneal inoculation with either the DA strain of Theiler's virus or Mengo virus, two members of the Cardiovirus genus. These CTLs contribute to viral clearance in the case of Theiler's virus but do not protect the mice from the fatal encephalomyelitis caused by Mengo virus. In this study we show that DA and Mengo virus-induced CTLs are cross-reactive. The cross-reactivity is due to a conserved, H-2D b-restricted epitope located between amino acid residues 122 and 130 of the VP2 capsid protein (VP2 122-130). This epitope is immunodominant in C57BL/6 mice infected with Theiler's virus. The VP2 122-130 epitope, initially identified for Mengo virus, is the first CTL epitope described for Theiler's virus.

In genetically susceptible strains of mice, the DA strain of Theiler's virus, a picornavirus, causes a persistent infection of the white matter of the spinal cord associated with chronic demyelination. In resistant strains, on the other hand, the infection is cleared within 1 to 2 weeks. In this article, we show that Theiler's virus induces a rapid and abundant cytotoxic T lymphocyte (CTL) response in resistant C57BL/6 mice, while the response remains low throughout infection in susceptible SJL/J mice. This difference can be referred to a higher number of virus-specific CTL precursors in C57BL/6 mice. These observations indicate that the efficient induction of virus-specific CTL precursors is critical for avoiding the establishment of a persistent picornaviral infection.

H-2b mice are resistant to persistent infection of the central nervous system by Theiler's virus. They clear the infection 7 to 10 days after intracranial inoculation. Resistance maps to the H-2D gene and not to the H-2K gene and is associated with a potent antiviral cytotoxic T-lymphocyte (CTL) response. We used H-2b mice in which theH-2D or the H-2K gene had been inactivated to dissect the respective roles of these genes in resistance. We report that H-2D −/− but notH-2K −/− mice were susceptible to persistent infection. Furthermore, whereas H-2K −/−mice mounted a vigorous virus-specific CTL response, similar to that of control C57BL/6 mice, the CTL response ofH-2D −/− mice was nil or minimal. Using target cells transfected with the H-2Db or theH-2Kb gene, we showed that theH-2K-restricted CTL response against the virus was minimal in H-2D −/− mice. These results demonstrate that the H-2Db andH-2Kb genes play nonredundant roles in the resistance to this persistent infection.

In vivo administration of interleukin-2 (IL-2)-secreting tumor cells results in complete protection against persistent infection by Theiler's murine encephalomyelitis virus (TMEV) in susceptible DBA/2 mice. The IL-2-mediated protection was found to depend on the inoculum size as well as the timing of IL-2 administration. IL-2-treated and TMEV-infected mice displayed a three-to fourfold relative increase in virus-specific cytotoxic T-lymphocyte (CTL) precursors. Thus, we postulate that the persistence of TMEV infection in susceptible mice reflects limited numbers of relevant CTL precursors and their time course of induction and activation.

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