Structural motifs in rheumatoid T-cell receptors

The linkage of rheumatoid arthritis (RA) to HLA-DR haplotypes, high levels of HLA-DR expression, and T-cell infiltration in the joints, indicate a central role for the interaction of T-cell receptors (TCR) with antigen (Ag) + major histocompatibility complex (MHC) complexes in pathogenesis. Receptor analysis in RA has uncovered a restricted heterogeneity of TCR transcripts, suggesting an antigen-driven response. We analyzed the sequence and structural features of RA-associated TCRs in light of the recently published TCR crystal structures. The surface-exposed residues of the third complementarity-determining region (CDR3s) showed preferential use of certain amino acid residues when sequences derived from synovial fluid or tissue were compared with those derived from peripheral blood, particularly for alpha chains. Sequence alignment of oligoclonal synovial TCR CDR3s revealed groupings with similar CDR3 lengths and amino acid compositions, which suggests shared antigen recognition. Given the limitations of analyzing TCR sequences without knowing their structures, we developed several in vivo-activated synovial-tissue Vbeta17 + RA T-cell clones. Two Vbeta17/V alpha7 clones with different CDR3 sequences were analyzed by molecular modeling. Although distinct topologic features were seen, a central patch of residues with similar chemical and geometric characteristics was present in both. Electrostatic maps revealed similar binding surfaces of both alpha domains and central patches, with differences in the beta domains. This suggests that an alpha-domain-focused binding trajectory would allow shared antigen recognition by these TCRs. These studies support recognition of a limited diversity of Ag + MHC complexes by synovial RA TCRs.