title: Molecular interactions between T cells and fibroblast-like synoviocytes: role of membrane tumor necrosis factor-alpha on cytokine-activated T cells.
abstract: The mechanism of fibroblast-like synoviocyte (FLS) transformation into an inflammatory phenotype in rheumatoid arthritis (RA) is not fully understood. FLS interactions with invading leukocytes, particularly T cells, are thought to be a critical component of this pathological process. Resting T cells and T cells activated through the T-cell receptor have previously been shown to induce inflammatory cytokine production by FLS. More recently, a distinct population of T cells has been identified in RA synovium that phenotypically resembles cytokine-activated T (Tck) cells. Using time lapse microscopy, the interactions of resting, superantigen-activated, and cytokine-activated T cells with FLS were visualized. Rapid and robust adhesion of Tck and superantigen-activated T cells to FLS was observed that resulted in flattening of the T cells and a crawling movement on the FLS surface. Tck also readily activated FLS to produce interleukin IL-6 and IL-8 in a cell contact-dependent manner that was enhanced by exogenous IL-17. Although LFA-1 and ICAM-1 co-localized at the Tck-FLS synapse, blocking the LFA-1/ICAM-1 interaction did not substantially inhibit Tck effector function. However, antibody blocking of membrane tumor necrosis factor (TNF)-alpha on the Tck surface did inhibit FLS cytokine production, thus illustrating a novel mechanism for involvement of TNF-alpha in cell-cell interactions in RA synovium and for the effectiveness of TNF-alpha blockade in the treatment of RA.
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, Rheumatic Disease Core Center, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Chinh N
authors.initials: CN
authors.lastname: Tran
authors.forename: Steven K
authors.initials: SK
authors.lastname: Lundy
authors.forename: Peter T
authors.initials: PT
authors.lastname: White
authors.forename: Judith L
authors.initials: JL
authors.lastname: Endres
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Motyl
authors.forename: Raj
authors.initials: R
authors.lastname: Gupta
authors.forename: Cailin M
authors.initials: CM
authors.lastname: Wilke
authors.forename: Eric A
authors.initials: EA
authors.lastname: Shelden
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Chung
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Urquhart
authors.forename: David A
authors.initials: DA
authors.lastname: Fox
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology; D002448:Cell Adhesion; D002450:Cell Communication; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D020381:Interleukin-17 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000494:pharmacology; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology*; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*