CLASS-II-RESTRICTED T-CELL RESPONSES IN THEILERS MURINE ENCEPHALOMYELITIS VIRUS-INDUCED DEMYELINATING DISEASE .5. MAPPING OF A DOMINANT IMMUNOPATHOLOGIC VP2 T-CELL EPITOPE IN SUSCEPTIBLE SJL J MICE/

Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease is a relevant mouse model of multiple sclerosis. Demyelination is linked to persistent TMEV infection of the central nervous system and characterized by perivascular inflammatory mononuclear infiltrates and primary demyelination. Myelin damage is a T cell-dependent proces s and susceptibility correlates with the temporal development of chron ic virus-specific delayed-type hypersensitivity (DTH) responses. Our p revious results have shown that inflammatory processes mediated by Th1 cells specific for a determinant(s) on virus capsid protein 2 (VP2) p lay a major immunopathologic role in SJL/J mice. This study identifies a 13 amino acid peptide on VP2 (VP74-86) as the immunodominant T cell epitope in TMEV-infected and-immunized SJL/J mice, and demonstrates t he ability of that sequence to prime for the majority of the SJL/J DTH T cell response to intact TMEV. The importance of T cell responses to this epitope in the demyelinating process was illustrated by experime nts in which SJL/J mice displayed an increased incidence and accelerat ed onset of clinical disease after peripheral immunization with a fusi on protein containing VP274-84 before intracerebral infection with a s uboptimal dose of the BeAn strain of TMEV. Identification of this immu nopathologic TMEV T cell epitope will be critically important for deli neation of the mechanisms of T cell-mediated myelin damage and for pot ential use to prevent and/or treat TMEV-induced demyelinating disease via the induction of epitope-specific tolerance.