title: Limited T-cell receptor beta-chain heterogeneity among interleukin 2 receptor-positive synovial T cells suggests a role for superantigen in rheumatoid arthritis.
abstract: Rheumatoid arthritis (RA) is a disease affecting the synovial membranes of articulating joints that is thought to result from T-cell-mediated autoimmune phenomena. T cells responsible for the pathogenesis of RA are likely present in that fraction of synovial T cells that expresses the interleukin 2 receptor (IL-2R), one marker of T-cell activation. We report herein an analysis of T-cell receptor (TCR) beta-chain gene expression by IL-2R-positive synovial T cells. These T cells were isolated from uncultured synovial tissue specimens by using IL-2R-specific monoclonal antibodies and magnetic beads, and TCR beta-chain transcription was analyzed by PCR-catalyzed amplification using a panel of primers specific for the human TCR beta-chain variable region (V beta). Multiple V beta gene families were found to be transcribed in these patients samples; however, three gene families, V beta 3, V beta 14, and V beta 17, were found in a majority of the five synovial samples analyzed, suggesting that T cells bearing these V beta s had been selectively retained in the synovial microenvironment. In many instances, the V beta 3, V beta 14, or V beta 17 repertoires amplified from an individual patient were dominated by a single rearrangement, indicative of clonal expansion in the synovium and supportive of a role for these T cells in RA. Of note is a high sequence similarity between V beta 3, V beta 14, and V beta 17 polypeptides, particularly in the fourth complementarity-determining region (CDR). Given that binding sites for superantigens have been mapped to the CDR4s of TCR beta chains, the synovial localization of T cells bearing V beta s with significant CDR4 homology indicates that V beta-specific T-cell activation by superantigen may play a role in RA.
authors.affiliation: Autoimmune Disease Program, Immune Response Corporation, Carlsbad, CA 92008.
authors.forename: M D
authors.initials: MD
authors.lastname: Howell
authors.forename: J P
authors.initials: JP
authors.lastname: Diveley
authors.forename: K A
authors.initials: KA
authors.lastname: Lundeen
authors.forename: A
authors.initials: A
authors.lastname: Esty
authors.forename: S T
authors.initials: ST
authors.lastname: Winters
authors.forename: D J
authors.initials: DJ
authors.lastname: Carlo
authors.forename: S W
authors.initials: SW
authors.lastname: Brostoff
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology*; D001483:Base Sequence; D003001:Cloning, Molecular; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor; D014644:Genetic Variation; D006684:HLA-DR Antigens / Q000032:analysis*; D006801:Humans; D046911:Macromolecular Substances; D051379:Mice; D008969:Molecular Sequence Data; D009693:Nucleic Acid Hybridization; D009838:Oligodeoxyribonucleotides; D016133:Polymerase Chain Reaction / Q000379:methods; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D012689:Sequence Homology, Nucleic Acid; D013583:Synovial Membrane / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014158:Transcription, Genetic
chemical_list: D006684:HLA-DR Antigens; D046911:Macromolecular Substances; D009838:Oligodeoxyribonucleotides; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015375:Receptors, Interleukin-2