Selection of T cell receptor Vβ elements by HLA‐DR determinants predisposing to Rheumatoid Arthritis

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Abstract
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.