Role of CD8+ T Cells in TMEV Resistance and Susceptibili

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Description (provided by applicant) ntracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) results in chronic inflammatory demyelination leading to clinical symptoms in susceptible mice. In light of the potential viral etiology and similarities in the progression of chronic demyelination, this TMEV system is considered to be one of the best animal models for studying human multiple sclerosis (MS). Extensive studies on the class II-restricted, CD4+ T cell response specific for TMEV, which appears to play an important role in viral pathogenesis, have been reported. Using X32-microglobulin and perforin deficient mice lacking cytotoxic T cell function, we have demonstrated that cytotoxic function is important for protection from this virus-induced demyelinating disease in resistant mice with the C57BL/6 background. However, very little is known about the class I-restricted, CD8+ T cell response against TMEV particularly in susceptible strains, although this type of response is known to be the most efficient in protecting the host from viral infections. During the past grant period, we have identified one major and two minor H-2Db-restricted CTL epitopes for resistant C57BL/6 mice, and similarly one predominant and two subdominant H-2Ks-restricted CTL epitopes for susceptible SJL/J mice using overlapping peptides of the entire capsid proteins of TMEV. Because resistance to TMEV-induced demyelination is associated with the H2D locus and susceptible mice lack virus-specific, H-2Drestricted cytotoxic T cells, we speculate that the efficiency and/or frequency of virus-specific CD8+ cytotoxic T cells may be dependent on the differences in the class I restriction between resistant and susceptible mice. We propose here to examine the role and fate of these cytotoxic T cells specific for the predominant and subdominant viral epitopes in resistance and/or susceptibility to Theiler's virusinduced demyelinating disease as a model for human multiple sclerosis. The specific aims for the proposed studies include: 1) To assess the level and fate of CD8+ T cells specific for viral epitopes in resistant and susceptible mice during the course of demyelinating disease; 2) To determine the role of virus-specific CD8+ T cells in protection from and/or pathogenesis of TMEV-induced demyelinating disease; 3) To examine the significance of H-2D vs H-2K-restriction for TMEV-specific CTL in resistance/susceptibility and the potential mechanism of this skewed restriction. We believe that our proposed studies will yield important information on the potential control mechanism(s) against virusinduced, immune-mediated demyelination, which is a relevant animal model for studying human MS.