LIMITED T-CELL RECEPTOR BETA-CHAIN HETEROGENEITY AMONG INTERLEUKIN-2 RECEPTOR-POSITIVE SYNOVIAL T-CELLS SUGGESTS A ROLE FOR SUPERANTIGEN IN RHEUMATOID-ARTHRITIS

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 patient 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.