T CELL RECEPTORS INVOLVED IN TMEV INDUCED DEMYELINATION

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Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) results in chronic inflammatory demyelination leading to clinical signs in susceptible mice. The TMEV system is considered to be a relevant infectious animal model, an alternative to the experimental autoimmune encephalomyelitis (EAE) system, for studying human multiple sclerosis (MS) in light of the potential viral etiology and similarities in the progression of chronic demyelination. Previously, we have identified major Th epitopes accounting for greater than 85 percent of the Th response to TMEV. In addition, we have identified the Th epitopes (VP1233-250 and VP274-86, but not VP324-37) involved in the pathogenesis of demyelination and their association to induce relatively high levels of Th responses. We have further observed that the Jbeta1 region polymorphism is associated with susceptibility to demyelination and that the susceptible H-2Ds MHC locus can override the resistant effect of the TCR beta-chain genotype. Furthermore, we have recently selected spontaneously arising non-pathogenic variant viruses containing a single amino acid substitution at position 244 within the major Th1 epitope, VP1233-250, resulting in a switch to Th2 response. Moreover, the initial demyelination induced by TMEV infection leads to the development of autoimmune Th response to a major myelin component. Our recent preliminary studies for spectratyping and TCR CDR3 analyses of infiltrating T cells in the CNS indicate that clonal expansion of certain T cell populations is apparent as early as 7 d after viral infection. Some of the major population appear to be persistent throughout the disease course. In comparison with CDR3 sequences of hybridomas with known specificity, these T cells represent virus- and/or autoantigen-reactive populations. Based on these preliminary results, we propose to correlate the TCR repertoire in the CNS with the development of TMEV-induced demyelination. Three specific aims are proposed in this application: (1) Correlation of the TCR repertoire in the CNS with the pathogenesis of TMEV-induced demyelination; (2) Role of virus- specific and autoreactive T cells in the pathogenesis of demyelination; and (3) Influence of additional Vbeta or resistant MHC class I genes in the selection of TCR repertoire in the CNS. We believe that our proposed studies will yield important information on the role of infiltrating T cell populations and their expansion in the pathogenesis of virus-induced, T cell-mediated demyelination, leading to the eventual development of autoimmunity to CNS autoantigens.