Mechanisms underlying the formation of the T cell receptor repertoire in 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 patients with rheumatoid arthritis, an HLA-DRB1 04-associated disease. By comparing frequencies of V beta-J beta combinations, healthy individuals segregated into independent clusters, which strongly correlated with the HLA-DRB1 allele expression. The repertoire fingerprint imposed by the HLA-DRB1 alleles involved only a selected group of J beta elements, 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 selection mechanism that significantly distorts the composition of the T cell receptor repertoire.
Walser-Kuntz
D R
DR
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Weyand
C M
CM
Weaver
A J
AJ
O'Fallon
W M
WM
Goronzy
J J
JJ
D000595:Amino Acid Sequence; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D016000:Cluster Analysis; D006684:HLA-DR Antigens / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009693:Nucleic Acid Hybridization; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis* / Q000235:genetics* / Q000276:immunology
D006684:HLA-DR Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta