A STRUCTURAL MODEL FOR TCR RECOGNITION OF THE HLA CLASS-II SHARED EPITOPE SEQUENCE IMPLICATED IN SUSCEPTIBILITY TO RHEUMATOID-ARTHRITIS

HLA molecules associated with rheumatoid arthritis (RA) contain a disc rete structural element known as the shared epitope, a set of conserve d amino acid residues located on the alpha helical portion of the clas s II beta chain. Each of the different HLA molecules associated with R A contain the same shared epitope sequence, although they may vary mar kedly in other regions of the class II structure, which also determine peptide-class II interactions. Previous mutagenesis studies and struc tural modelling indicate that key polymorphic amino acid side chains w ithin the shared epitope sequence are in locations likely to contact t he T cell receptor (TCR) during the trimolecular activation reaction b etween the HLA-peptide complex and TCR. We have evaluated the potentia l structural basis for such shared epitope recognition by analysing de tailed molecular models of the arthritis-associated DRB10404 molecule and a T cell receptor from T cell clone EM025, specific for HLA-DR4 m olecules which carry the shared epitope. A likely orientation for the trimolecular complex was deduced in which the EM025 alpha chain intera cts with the DR alpha chain and the EM025 beta chain interacts with th e DR beta chain; residues Q70 and R71 within the DR beta chain shared epitope region are positioned for hydrogen bond interactions directly with Q97 of the TCR beta CDR3 region, D30 of the TCR beta CDR1 region, and possibly N51 of the TCR beta CDR2 region, indicating a degree of specific selection and interaction which encompasses multiple TCR cont acts. These findings suggest a structural basis for the genetic associ ations with the HLA shared epitope and the potential contribution of t his region to oligoclonal T cell selection and expansion in RA. (C) 19 96 Academic Press Limited