Class II-restricted T cell responses in Theiler's murine encephalomyelitis virus-induced demyelinating disease. VI. Potentiation of demyelination with and characterization of an immunopathologic CD4+ T cell line specific for an immunodominant VP2 epitope.

Abstract

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. Our previous results have shown that susceptibility correlates with the temporal development of chronic virus-specific delayed-type hypersensitivity (DTH) responses and suggest that inflammatory processes mediated by T cells specific for an immunodominant determinant on virus capsid protein 2 (VP2(74-86)) play a major immunopathologic role in SJL/J mice. In this study we have further defined the T cell-dependent nature and specificity of the demyelinating process in susceptible SJL/J mice by showing that thymectomized irradiated bone marrow-restored mice fail to develop chronic demyelination and that i.v. adoptive transfer of polyclonal TMEV-specific T cells before intracerebral infection with a suboptimal dose of the BeAn strain of TMEV led to increased incidence and accelerated onset of clinical disease. The data also show that demyelination is dependent on the activity of virus-specific CD4+ T cells because in vivo depletion with anti-CD4, but not anti-CD8, mAb led to significantly diminished incidence and severity of demyelination concomitant with a decrease in TMEV-specific DTH reactivity. In addition, the adoptive transfer of a TMEV-specific, DTH-mediating CD4+ I-A(s)-restricted Th1 line (sTV1) specific for the immunodominant VP2(74-86) epitope also led to increased incidence and accelerated onset of clinical disease only in TMEV-infected recipients. Collectively, the results of this and the companion paper demonstrate the highly significant immunopathologic contribution of CD4+ T cell responses specific for an immunodominant viral epitope to the chronic central nervous system demyelination observed in TMEV-infected SJL/J mice.