SELECTION OF T-CELL RECEPTOR-V-BETA ELEMENTS BY HLA-DR DETERMINANTS PREDISPOSING TO RHEUMATOID-ARTHRITIS

Objective. Rheumatoid arthritis (RA) is genetically linked to a sequence motif encoding for the middle portion of the alpha-helical loop, which is adjacent to the antigen-binding groove of the HLA-DR molecule. The disease-associated element might be involved in binding the antigen or in interacting with the T cell receptor (TCR). To investigate the contribution of the disease-associated element in T cell recognition events, we studied structural requirements in the interaction of T cell clones with HLA-DR determinants. Methods. T cell clones restricted to disease-associated HLA-DR determinants were established by allogeneic stimulation of HLA-DRB1*0401+ or *0401-responders with HLA-DRB1*0404/8+ stimulators. Allele-specific primer sets were used to identify the Vbeta gene segment expressed by individual clones. Sequence analysis was applied to study the diversity of the TCR beta-chain junctional regions. Results. The repertoire of TCR Vbeta elements was strongly biased toward the usage of Vbeta6. HLADRB1* 0401+ and *0401- donors preferentially recruited Vbeta6+ T cells to recognize the disease-associated HLA-DR determinant. Sequence data revealed that the Vbeta6.6/7 and Vbeta6.8/9 subtypes of the Vbeta6 multigene family were overrepresented. The TCR beta chains were characterized by a high degree of junctional diversity, supporting the view that a multitude of peptide-DR complexes were recognized and that the preferential use of Vbeta6 was dictated by the TCR beta chain-DRbeta1 chain contact. Conclusion. T cells reactive with the disease-associated HLA-DR structure are nonrandomly selected. The HLA-DR component predisposing to RA might define molecular requirements that restrict the TCR-HLA interaction. Thus, the phenomenon of HLA association in RA might reflect a genetic control of T cell recognition, through the selection of the TCR repertoire.