title: Displacement of linker for activation of T cells from the plasma membrane due to redox balance alterations results in hyporesponsiveness of synovial fluid T lymphocytes in rheumatoid arthritis.
abstract: The T lymphocytes that reside in the synovium of the inflamed joints in patients with rheumatoid arthritis display severe hyporesponsiveness upon antigenic stimulation, which is probably due to their constant subjection to high levels of oxidative stress. Here we report that the synovial fluid T lymphocytes exert severely impaired phosphorylation of the adaptor protein linker for activation of T cells (LAT), a crucial component of the TCR-mediated signaling pathways. In healthy T lymphocytes, LAT is a membrane-bound protein and becomes phosphorylated by zeta-associated protein of 70 kDa (ZAP-70) upon TCR engagement. The molecular basis underlying the deficient phosphorylation of LAT and consequently the hyporesponsiveness of the synovial fluid T lymphocytes lies in the membrane displacement of LAT. We demonstrate that the subcellular localization of LAT is sensitive to changes in the intracellular levels of the antioxidant glutathione. The membrane anchorage of LAT, and consequently the phosphorylation of LAT and the cellular activation of the synovial fluid T lymphocytes upon TCR engagement, is restored in synovial fluid T lymphocytes after supplementation of the intracellular glutathione levels with N-acetyl-l -cysteine. These data suggest a role for the membrane displacement of LAT in the hyporesponsiveness of the synovial fluid T lymphocytes as a consequence of oxidative stress.
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. gringhuis@mail.medfac.leidenuniv.nl
authors.forename: S I
authors.initials: SI
authors.lastname: Gringhuis
authors.forename: A
authors.initials: A
authors.lastname: Leow
authors.forename: E A
authors.initials: EA
authors.lastname: Papendrecht-Van Der Voort
authors.forename: P H
authors.initials: PH
authors.lastname: Remans
authors.forename: F C
authors.initials: FC
authors.lastname: Breedveld
authors.forename: C L
authors.initials: CL
authors.lastname: Verweij
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000276:immunology* / Q000378:metabolism; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D003593:Cytoplasm / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000378:metabolism; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D010084:Oxidation-Reduction; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013582:Synovial Fluid / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D007376:Interleukin-2; D007527:Isoenzymes; C110810:LAT protein, human; D008565:Membrane Proteins; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D005978:Glutathione