STRUCTURAL MOTIFS IN RHEUMATOID T-CELL RECEPTORS

The linkage of rheumatoid arthritis (RA) to HLA-DR haplotypes, high le vels of HLA-DR expression, and T-cell infiltration in the joints, indi cate a central role for the interaction of T-cell receptors (TCR) with antigen (Ag) + major histocompatibility complex (MHC) complexes in pa thogenesis. Receptor analysis in RA has uncovered a restricted heterog eneity of TCR transcripts, suggesting an antigen-driven response, We a nalyzed the sequence and structural features of RA-associated TCRs in light of the recently published TCR crystal structures, The surface-ex posed residues of the third complementarity-determining region (CDR3s) showed preferential use of certain amino acid residues when sequences derived from synovial fluid or tissue mere compared with those derive d from peripheral blood, particularly for alpha chains, Sequence align ment of oligoclonal synovial TCR CDR3s revealed groupings with similar CDR3 lengths and amino acid compositions, which suggests shared antig en recognition, Given the limitations of analyzing TCR sequences witho ut knowing their structures, we developed several in vivo-activated sy novial-tissue V beta 17+RA T-cell clones, Two V beta 17/V alpha 7 clon es with different CDR3 sequences were analyzed by molecular modeling, Although distinct topologic features were seen, a central patch of res idues 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 domain s, 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.