Search

Infection of the central nervous system (CNS) with Theiler's murine encephalomyelitis virus (TMEV) induces an immune-mediated demyelinating disease in susceptible mouse strains such as SJL/J (H-2(s)) but not in strains such as C57BL/6 (H-2(b)). In addition, it has been shown that (C57BL/6 × SJL/J)F1 mice (F1 mice), which carry both resistant and susceptible MHC haplotypes (H-2(b/s)), are resistant to both viral persistence and TMEV-induced demyelinating disease. In this study, we further analyzed the immune responses underlying the resistance of F1 mice. Our study shows that the resistance of F1 mice is associated with a higher level of the initial virus-specific H-2(b)-restricted CD8(+) T cell responses than of the H-2(s)-restricted CD8(+) T cell responses. In contrast, pathogenic Th17 responses to viral epitopes are lower in F1 mice than in susceptible SJL/J mice. Dominant effects of resistant genes expressed in antigen-presenting cells of F1 mice on regulation of viral replication and induction of protective T cell responses appear to play a crucial role in disease resistance. Although the F1 mice are resistant to disease, the level of viral RNA in the CNS was intermediate between those of SJL/J and C57BL/6 mice, indicating the presence of a threshold of viral expression for pathogenesis.

Theiler's murine encephalomyelitis virus (TMEV)-induced immune-mediated demyelinating disease in susceptible mouse strains has been extensively investigated as a relevant model for human multiple sclerosis. Previous investigations of antiviral T-cell responses focus on immune responses to viral capsid proteins, while virtually nothing is reported on immune responses to nonstructural proteins. In this study, we have identified noncapsid regions recognized by CD4(+) T cells from TMEV-infected mice using an overlapping peptide library. Interestingly, a greater number of CD4(+) T cells recognizing an epitope (3D(21-36)) of the 3D viral RNA polymerase, in contrast to capsid epitopes, were detected in the CNS of TMEV-infected SJL mice, whereas only a minor population of CD4(+) T cells from infected C57BL/6 mice recognized this region. The effects of preimmunization and tolerization with these epitopes on the development of demyelinating disease indicated that capsid-specific CD4(+) T cells are protective during the early stages of viral infection, whereas 3D(21-36)-specific CD4(+) T cells exacerbate disease development. Therefore, protective versus pathogenic CD4(+) T-cell responses directed to TMEV appear to be epitope dependent, and the differences in CD4(+) T-cell responses to these epitopes between susceptible and resistant mice may play an important role in the resistance or susceptibility to virally induced demyelinating disease.