Selection of T cell receptor Vβ 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 α‐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 Vβ gene segment expressed by individual clones. Sequence analysis was applied to study the diversity of the TCR β‐chain junctional regions. Results. The repertoire of TCR Vβ elements was strongly biased toward the usage of Vβ6. HLA–DRB1*0401+ and *0401– donors preferentially recruited Vβ6+ T cells to recognize the disease‐associated HLA–DR determinant. Sequence data revealed that the Vβ6.6/7 and Vβ6.8/9 subtypes of the Vβ6 multigene family were overrepresented. The TCR β 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 Vβ6 was dictated by the TCR β chain–DRβ1 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.