ROLE OF T-CELL RECEPTOR-V-BETA GENES IN THEILERS VIRUS-INDUCED DEMYELINATION OF MICE

Intracerebral infection of certain strains of mice with Theiler's virus results in chronic immune-mediated demyelination in spinal cord. We used mouse mutants with deletion of the V-beta class of TCR genes to examine the role of TCR genes in this demyelinating disease which is similar to multiple sclerosis. Quantitative analysis of spinal cord lesions demonstrated a markedly increased number and extent of demyelinated lesions in persistently infected RIII S/J mice which have a massive deletion of the TCR V-beta-chain (V-beta-5.2, V-beta-8.3, V-beta-5.1, V-beta-8.2, V-beta-5.3, V-beta-8.1, V-beta-13, V-beta-12, V-beta-11, V-beta-9, V-beta-6, V-beta-15, V-beta-17) compared with B10.RIII mice which are of identical MHC haplotype (H-2r) but have normal complement of V-beta TCR genes. In contrast, infection of C57L (H-2b) or C57BR (H-2k) mice which have deletion of the V-beta TCR genes (V-beta-5.2, V-beta-8.3, V-beta-5.1, V-beta-8.2, V-beta-5.3, V-beta-8.1, V-beta-13, V-beta-12, V-beta-11, and V-beta-9) resulted in few demyelinating lesions. Genetic segregation analysis of (B10.RIII x RIII S/J) x RIII S/J backcrossed mice and (B10.RIII x RIII S/J) F2 mice demonstrated correlation of increased susceptibility to demyelination with deletion of TCR V-beta genes. The increase in number of demyelinating lesions correlated with increase in number of virus-Ag+ cells in spinal cord. These experiments provide strong evidence that the structural diversity at the TCR beta-complex can influence susceptibility to virus-induced demyelination.