CDR3 sequence motifs shared by oligoclonal rheumatoid arthritis synovial T cells: Evidence for an antigen-driven response

Abstract

T lymphocytes reactive with as yet undefined joint-localized foreign or autoantigens may be important in the pathogenesis of RA. Molecular studies demonstrating skewed T cell antigen receptor (TCR) variable gene usage and selective expansion of particular T cell clones within the synovial compartment support this view. Based on our recent study documenting selective expansion of Vβ17+ T cells in RA, we have pursued the identification of T cells relevant to the disease process, in an informative patient, by combining molecular analysis of freshly explanted RA synovial tissue Vβ17 TCR transcripts with in vitro expansion of Vβ17+ synovial tissue T cell clones. Peripheral blood Vβ17 cDNA transcripts proved heterogeneous. In contrast, two closely related sequences, not found in the peripheral blood, dominated synovial tissue Vβ17 transcripts, suggesting selective localization and oligoclonal expansion at the site of pathology. CD4+, Vβ17+ synovial tissue-derived T cell clones, isolated and grown in vitro, were found to express TCR β chain transcripts homologous to the dominant Vβ17 synovial tissue sequences. One clone shares with a dominant synovial tissue sequence a conserved cluster of 4/5 amino acids (IGQ-N) in the highly diverse antigen binding CDR3 region, suggesting that the T cells from which these transcripts derive may recognize the same antigen. These findings have permitted a complete characterization of the α/ β TCR expressed by putatively pathogenic T cell clones in RA. Functional analysis suggests that the conserved CDR3 sequence may confer specificity for, or restriction by, the MHC class II antigen, DR4.