A potential role for protein tyrosine kinase p56lck in rheumatoid arthritis synovial fluid T lymphocyte hyporesponsiveness

Rheumatoid arthritis (RA) synovial fluid (SF)-T lymphocytes appear relatively inactive in situ and respond only weakly to diverse stimuli ex vivo. To characterize the molecular defects underlying this hyporesponsiveness we analyzed the expression level of several proteins involved in TCR-proximal signal transduction, As compared to peripheral blood (PB)-T lymphocytes, SF-T cells from some (but not all) of the patients analyzed expressed lower levels of TCR alpha beta, CD3 epsilon, TCR zeta, p56(lck) and LAT, while p59(fyn), phospholipase C-gamma1 and ZAP-70 expression was unaltered. Semi-quantitative analysis of T cells from several patients revealed that the degree of TCR zeta; chain and p56(lck) modulation correlated statistically significantly with the level of SF-T cell hyporesponsiveness, The differential reactivity of p56(lck) specific monoclonal and polyclonal antibodies in SF-T but not PB-T lymphocytes indicated that p56(lck) modulation consists of a conformational change rather than loss of expression. Our results indicate that multiple signaling molecules can be modulated in RA SF-T cells and show for the first time a direct quantitative correlation between T cell hyporesponsiveness and modulation of TCR zeta and of p56(lck), a critical protein tyrosine kinase required for T cell activation.