title: Down-regulation of the T cell receptor CD3 zeta chain in rheumatoid arthritis (RA) and its influence on T cell responsiveness.
abstract: T cells implicated in chronic inflammatory diseases such as RA respond weakly when stimulated in vitro with mitogen or antigen. The mechanism behind this hyporesponsiveness is unclear, but a depressed expression of the T cell receptor (TCR)-associated CD3zeta chain has been suggested. In the present work we describe a low expression of CD3zeta in synovial fluid (SF) T cells from RA patients compared with peripheral blood (PB) T cells, but no difference in CD3zeta 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 CD3zeta. Through stimulation with anti-CD3 antibodies we demonstrated that the TCR-dependent proliferative response was decreased in SF T cells compared with PB T cells. Stimulation with phorbol ester and ionomycin also resulted in a low proliferative response 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 similar 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 acetate (PMA)/ionomycin, in contrast to the diminished IFN-gamma response observed after stimulation with anti-CD3. This indicates that the hyporesponsiveness of SF T cells can not be generalized to all T cell functions. The differential response to external stimuli is likely to be of importance for the capacity of SF T cells to influence inflammatory reactions.
authors.affiliation: Department of Medicine, Unit of Rheumatology, Karolinska Institute, Stockholm, Sweden. Louise.Berg@cmm.ki.se
authors.forename: L
authors.initials: L
authors.lastname: Berg
authors.forename: J
authors.initials: J
authors.lastname: Rönnelid
authors.forename: L
authors.initials: L
authors.lastname: Klareskog
authors.forename: A
authors.initials: A
authors.lastname: Bucht
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism; D017252:CD3 Complex / Q000096:biosynthesis* / Q000502:physiology; D002455:Cell Division / Q000276:immunology; D016207:Cytokines / Q000032:analysis / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology*; D005260:Female; D006098:Granulocytes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism*; D013582:Synovial Fluid / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*
chemical_list: D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D016207:Cytokines; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D007371:Interferon-gamma