MECHANISMS UNDERLYING THE FORMATION OF THE T-CELL RECEPTOR REPERTOIREIN RHEUMATOID-ARTHRITIS

The contributions of germline-encoded T cell receptor segments and of HLA-DR polymorphisms in shaping the repertoire of human CD4(+) CD45RO( -) T cells were investigated In healthy unrelated individuals and in p atients with rheumatoid arthritis, an HLA-DRB1()04-associated disease . By comparing frequencies of V beta-J beta combinations, healthy indi viduals segregated into independent clusters, which strongly correlate d with the HLA-DRB1 allele expression. The repertoire fingerprint impo sed by the HLA-DRB1 alleles involved only a selected group of J beta e lements, whereas the distribution of the other J beta segments was HLA independent. The HLA-restricted J beta elements are characterized by a Gly-Pro-Gly sequence within the conserved Phe-Gly-X-Gly motif, which induces rigidity in an otherwise more flexible protein backbone. The T cell receptor repertoire distinguished patients with RA from healthy HLA-DR-matched individuals, suggesting that patients share a selectio n mechanism that significantly distorts the composition of the T cell receptor repertoire.