Down-regulation of the T cell receptor CD3 zeta chain in rheumatoid arthritis (RA) and its influence on T cell responsiveness

T cells implicated in chronic inflammatory diseases such as RA respond weak ly when stimulated in vitro with mitogen or antigen. The mechanism behind t his hyporesponsiveness is unclear, but a depressed expression of the T cell receptor (TCR)-associated CD3 zeta chain has been suggested. In the presen t work we describe a low expression of CD3 zeta in synovial fluid (SF) T ce lls from RA patients compared with peripheral blood (PB) T cells, but no di fference in CD3 zeta expression between RA and healthy control PB T cells. In vitro studies demonstrated that granulocytes but not SF macrophages are able to down-regulate the expression of CD3 zeta. Through stimulation with anti-CD3 antibodies we demonstrated that the TCR-dependent proliferative re sponse was decreased in SF T cells compared with PB T cells. Stimulation wi th phorbol ester and ionomycin also resulted in a low proliferative respons e of SF T cells, indicating that both signal transduction through the TCR ( stimulation with anti-CD3) and events further downstream in the signalling pathways (stimulation with phorbol ester and ionomycin) are affected. A sim ilar depression of T cell activity was observed when induction of IL-2 and IL-4 was measured. However, SF T cells were not defective in the induction of interferon-gamma (IFN-gamma) when stimulated with phorbol myristate acet ate (PMA)/ionomycin, in contrast to the diminished IFN-gamma response obser ved after stimulation with anti-CD3. This indicates that the hyporesponsive ness of SF T cells can not be generalized to all T cell functions. The diff erential response to external stimuli is likely to be of importance for the capacity of SF T cells to influence inflammatory reactions.