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.

Clonal expansion of mycobacterial heat‐shock protein–reactive T lymphocytes in the synovial fluid and blood of rheumatoid arthritis patients

“…This biased V gene pattern is due to the selective expansion of a monoclonal or oligoclonal T cell population(s) in patients with RA. The majority of predominant TCR AV and BV gene families expressed by hsp65-specific T cells from RA patients seen in our study correspond to the V genes found to be overexpressed in rheumatoid synovium (19,20,25,26).…”

“…Supporting evidence includes the HLA-DR association of the disease and the infiltration of T lymphocytes found in the lesions. There is evidence suggesting an overexpression of certain TCR V gene families among infiltrating T cells obtained from rheumatoid synovium (18)(19)(20). It is a subject of controversy, however, whether these infiltrating T cells are of oligoclonal or polyclonal origin (19,21,22), and their antigen specificity remains a matter of speculation.…”

Alterations of the synovial T cell repertoire in anti–citrullinated protein antibody–positive rheumatoid arthritis

“…These studies have provided a number of crucial insights. First, both the V ␤ usage and the T cell clonality appeared to be skewed in RA (45). Second, this skewing is a primary event, rather than merely a consequence of inflamma- tion, since the unaffected siblings of RA patients also display expanded T cell clonotypes (46,47).…”

Pristane, a Non-Antigenic Adjuvant, Induces MHC Class II-Restricted, Arthritogenic T Cells in the Rat

“…The joint-restricted CD4 ϩ T cell clonotypes that persist over time are preferentially found in the CD25 ϩ subpopulation (5). Skewing of the TCRV␤ repertoire (e.g., V␤3, V␤14 ␣ ␦ V␤17) has been shown to occur frequently in CD25 ϩ T cells in the synovial fluid, indicating a local activation by a common antigenic stimuli (6). However, it has been difficult to identify clones of arthritogenic T cells or a common Ag in the joint that could explain the development of arthritis, and the pathogenic function of infiltrating T cells into the joint synovia is still uncertain.…”