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 V beta 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 V beta elements was strongly biased toward the usage of V beta 6. HLA-DRB1*0401+ and *0401- donors preferentially recruited V beta 6+ T cells to recognize the disease-associated HLA-DR determinant. Sequence data revealed that the V beta 6.6/7 and V beta 6.8/9 subtypes of the V beta 6 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 V beta 6 was dictated by the TCR beta chain-DR beta 1 chain contact.


CONCLUSIONS
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.
Weyand
C M
CM
Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905.
Oppitz
U
U
Hicok
K
K
Goronzy
J J
JJ
D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology*; D003429:Cross Reactions; D000939:Epitopes / Q000235:genetics* / Q000276:immunology; D005802:Genes, MHC Class II; D006684:HLA-DR Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D000939:Epitopes; D006684:HLA-DR Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta