Theiler's virus infection induces a predominant pathogenic CD4⁺ T cell response to RNA polymerase in susceptible SJL/J mice

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.