Multiple mechanisms support oligoclonal T cell expansion in rheumatoid synovitis

Background: The synovial T cell infiltrate in rheumatoid arthritis (RA) is diverse but contains clonally expanded CD4(+) populations. Recent reports; have emphasized that RA patients have a tendency to develop CD4(+) T cell oligoclonality which also manifests in the peripheral blood. Clonal dominance in the tissue may thus result from antigen specific stimulation in the synovial membrane or map reflect the infiltration of expanded clonotypes present throughout the lymphoid system. We have explored to what extent clonal populations amongst tissue CD4(+) T cells display joint specificity as defined by their restriction to the joint, their persistence over time, and their expression of markers indicative for local activation. Materials and Methods: Matched samples of peripheral blood and synovial fluid or synovial tissue were collected from 14 patients with active RA and CD4(+) IL-2R(+) and CD4(+) IL-2R(-) T cells from both compartments were purified. Clonal populations of CD4(+) T cells were detected by RT-PCR amplification of T cell receptor (TCR) transcripts with BV and BJ specific primers followed by size fractionation and direct sequencing of dominant size classes of TCR transcripts. Results: Clonal CD4(+) T cells were detected in the synovial fluid and synovial tissue of all patients. All patients carried synovial clonotypes that were undetectable in the blood but were present in independent joints or at several non-adjacent areas of the same joint. These joint restricted CD4(+) clonotypes were generally small in size, were preferentially found in the IL-2R(+) subpopulation, and persisted over time. A secund type of clonogenic T cells in the synovial infiltrate had an unrestricted tissue distribution and was present at similar frequencies amongst activated and nonactivated T cells in the blood and affected joints. Ubiquitous clonotypes isolated from two different patients expressed sequence homologies of the TCR beta chain. Conclusions: Two types of expanded CD4(+) clonotypes contribute to the T cell infiltrate in rheumatoid synovitis. Differences in the distribution pattern and in molecular features suggest that distinct mechanisms are supporting the clonal outgrowth of these two groups of clonotypes. Clonally expanded T cells restricted to the joint but present in several independent joints appear to respond to locally residing antigens. Clonogenic cells with an unrestricted distribution pattern and widespread activation in the blood and tissue map react. to a different class of antigens which appear to be shared by multiple patients. T cell recognition in RA may be involved at several different levels and may be related to more than one pathomechanism.