DEFECTIVE TCR-MEDIATED SIGNALING IN SYNOVIAL T-CELLS IN RHEUMATOID-ARTHRITIS

In rheumatoid arthritis (RA), the functional status of T cells is inco mpletely understood. Synovial T cells display phenotypic evidence of f ormer activation, but there is poor production of T cell-derived cytok ines in the synovium. In addition, synovial T cell proliferation upon mitogenic and antigenic stimulation was decreased compared with that i n peripheral blood T cells. Moreover, previous reports revealed that e arly Ca2+ rises induced by TCR/CD3 stimulation were decreased in RA T cells compared with those in healthy controls. To investigate the mole cular mechanisms of RA synovial T cell hyporesponsiveness, we analyzed the TCR/CD3-mediated protein tyrosine phosphorylation in RA periphera l blood and synovial fluid (SF) T cells. SF T cells exhibited a decrea sed overall tyrosine phosphorylation pattern upon stimulation. Most no tably, the induction of phosphorylation of p38 was virtually absent. M oreover, we found that tyrosine phosphorylation of the TCR zeta-chain, one of the most proximal events in TCR signaling, is clearly diminish ed in RA SF T cells. The decrease in tyrosine phosphorylation was acco mpanied by a decrease in detectable levels of zeta-protein within syno vial T cells. These results suggest that a defective TCR signaling und erlies the hyporesponsiveness of synovial T cells in RA.