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 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 TCRalphabeta, CD3epsilon, TCRzeta, 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 TCRzeta 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 TCRzeta and of p56(lck), a critical protein tyrosine kinase required for T cell activation.
Tolerance and Autoimmunity Section, INSERM U395, IFR 30, CHU Purpan, BP 3028, 31024 Toulouse Cedex 3, France.
P
P
Romagnoli
D
D
Strahan
M
M
Pelosi
A
A
Cantagrel
J P
JP
van Meerwijk
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000276:immunology; D001327:Autoimmune Diseases / Q000201:enzymology* / Q000276:immunology; D017252:CD3 Complex; D023082:Defensins; D005260:Female; D006801:Humans; D007719:Knee Joint; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000276:immunology; D008875:Middle Aged; D010940:Plant Proteins; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000032:analysis / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D013582:Synovial Fluid / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; C115335:CD3E protein, human; D023082:Defensins; D008565:Membrane Proteins; D010940:Plant Proteins; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; C054979:antigen T cell receptor, zeta chain; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)