title: Senescence marker killer cell lectin-like receptor G1 (KLRG1) contributes to TNF-α production by interaction with its soluble E-cadherin ligand in chronically inflamed joints.
abstract: OBJECTIVE
  Killer cell lectin-like receptor G1 (KLRG1) is an NK cell marker also expressed on T cells showing an immunosenescent phenotype. KLRG1 binding to its ligand E-cadherin inhibits functional responses. It was recently shown that soluble E-cadherin (sE-cadherin) also influences KLRG1 signalling, although its involvement in arthritis is unknown. Our goal was to evaluate the contribution of KLRG1(+) T cells to synovitis.
  
  
  METHODS
  Paired peripheral blood (PB) and synovial fluid (SF) mononuclear cells from 21 patients with spondyloarthritis (SpA) or rheumatoid arthritis (RA), eight with crystal-induced arthritis and 10 controls were obtained. T cells were characterised for KLRG1 expression directly ex vivo, while TNF-α/IFN-γ production was assessed after polyclonal stimulation. Assays of chemotaxis response towards SF were conducted. Additionally, sE-cadherin levels in our paired samples were determined. Moreover, TNF-α/IFN-γ production by antigen-specific T cells was evaluated in the presence of sE-cadherin.
  
  
  RESULTS
  KLRG1(+) T cells were enriched in SF as opposed to PB of SpA and RA patients, which contrasts with results obtained in crystal-induced arthritides. KLRG1(+) T cells were more functionally active as opposed to KLRG1(-) T cells and migrated preferentially towards SpA and RA SF. sE-cadherin levels were higher in SF versus plasma. The presence of sE-cadherin enhanced the number of KLRG1(+) CD4(+) T cells able to produce TNF-α but not IFN-γ.
  
  
  CONCLUSIONS
  sE-cadherin contributes to the local proinflammatory environment in the joint by favouring TNF-α production by KLRG1(+) CD4(+) T cells. This pathway seems to be operational in both SpA and RA, but not in crystal-induced arthritis.
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Rheumatology, Laboratory for Molecular Immunology and Inflammation, Ghent University Hospital, , Ghent, Belgium.
authors.forename: Lode
authors.initials: L
authors.lastname: Melis
authors.forename: Liesbet
authors.initials: L
authors.lastname: Van Praet
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Pircher
authors.forename: Koen
authors.initials: K
authors.lastname: Venken
authors.forename: Dirk
authors.initials: D
authors.lastname: Elewaut
mesh_terms: D000328:Adult; D000368:Aged; D015210:Arthritis, Gouty / Q000276:immunology / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism; D015820:Cadherins / Q000276:immunology / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000276:immunology; D002633:Chemotaxis / Q000276:immunology; D002805:Chondrocalcinosis / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000276:immunology / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008024:Ligands; D008297:Male; D008875:Middle Aged; D011971:Receptors, Immunologic; D025241:Spondylarthritis / Q000276:immunology* / Q000378:metabolism; D013582:Synovial Fluid / Q000166:cytology; D013585:Synovitis / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015534:Trans-Activators / Q000276:immunology / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000276:immunology
chemical_list: D015820:Cadherins; C573415:IFNG protein, human; C113413:KLRG1 protein, human; D037181:Lectins, C-Type; D008024:Ligands; D011971:Receptors, Immunologic; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: Arthritis; Rheumatoid Arthritis; Spondyloarthritis; Synovial fluid; TNF-alpha