Diverse Fine Specificity and Receptor Repertoire of T Cells Reactive to the Major VP1 Epitope (VP1230–250) of Theiler’s Virus: Vβ Restriction Correlates with T Cell Recognition of the C-Terminal Residue

Abstract

AbstractTheiler’s murine encephalomyelitis virus induces chronic demyelinating disease in genetically susceptible mice. The histopathological and immunological manifestation of the disease closely resembles human multiple sclerosis, and, thus, this system serves as a relevant infectious model for multiple sclerosis. The pathogenesis of demyelination appears to be mediated by the inflammatory Th1 response to viral epitopes. In this study, T cell repertoire reactive to the major pathogenic VP1 epitope region (VP1233–250) was analyzed. Diverse minimal T cell epitopes were found within this region, and yet close to 50% of the VP1-reactive T cell hybridomas used Vβ16. The majority (8/11) of the Vβ16+ T cells required the C-terminal amino acid residue on the epitope, valine at position 245, and every T cell hybridoma recognizing this C-terminal residue expressed Vβ16. However, the complementarity-determining region 3 sequences of the Vβ16+ T cell hybridomas were markedly heterogeneous. In contrast, such a restriction was not found in the Vα usage. Only restricted residues at this C-terminal position allowed for T cell activation, suggesting that Vβ16 may recognize 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. Thus, recognition of the C-terminal residue of a minimal T cell epitope may associate with a particular Vβ (but not Vα) subfamily-specific sequence, resulting in a highly restricted Vβ repertoire of the epitope-specific T cells.