A potential role for protein tyrosine kinase p56(lck) in rheumatoid arthritis synovial fluid T lymphocyte hyporesponsiveness

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