Diverse fine specificity and receptor repertoire of T cells reactive to the major VP1 epitope (VP1(230-250)) of Theiler's virus: V beta restriction correlates with T cell recognition of the C-terminal residue

Theiler's murine encephalomyelitis virus induces chronic demyelinating dise ase in genetically susceptible mice, The histopathological and immunologica l manifestation of the disease closely resembles human multiple sclerosis, and, thus, this system serves as a relevant infectious model for multiple s clerosis, The pathogenesis of demyelination appears to be mediated by the i nflammatory Th1 response to viral epitopes. In this study, T cell repertoir e reactive to the major pathogenic VP1 epitope region (VP1(233-250)) was an alyzed. Diverse minimal T cell epitopes were found within this region, and yet close to 50% of the VP1-reactive T cell hybridomas used V beta 16, The majority (8/11) of the V beta 16(+) T cells required the C-terminal amino a cid residue on the epitope, valine at position 245, and every T cell hybrid oma recognizing this C-terminal residue expressed V beta 16, However, the c omplementarity-determining region 3 sequences of the V beta 16(+) T cell hy bridomas were markedly heterogeneous, In contrast, such a restriction was n ot found in the V alpha usage, Only restricted residues at this C-terminal position allowed for T cell activation, suggesting that V beta 16 may recog nize this terminal residue. Further functional competition analysis for TCR and MHC class II-contacting residues indicate that many different residues can be involved in the class II and/or TCR binding depending on the T cell population, even if they recognize the identical minimal epitope region. T hus, recognition of the C-terminal residue of a minimal T cell epitope may associate with a particular V beta (but not V alpha) subfamily-specific seq uence, resulting in a highly restricted V beta repertoire of the epitope-sp ecific T cells.