title: Differential survival of leukocyte subsets mediated by synovial, bone marrow, and skin fibroblasts: site-specific versus activation-dependent survival of T cells and neutrophils.
abstract: OBJECTIVE
  Synovial fibroblasts share a number of phenotype markers with fibroblasts derived from bone marrow. In this study we investigated the role of matched fibroblasts obtained from 3 different sources (bone marrow, synovium, and skin) to test the hypothesis that synovial fibroblasts share similarities with bone marrow-derived fibroblasts in terms of their ability to support survival of T cells and neutrophils.
  
  
  METHODS
  Matched synovial, bone marrow, and skin fibroblasts were established from 8 different patients with rheumatoid arthritis who were undergoing knee or hip surgery. Resting or activated fibroblasts were cocultured with either CD4 T cells or neutrophils, and the degree of leukocyte survival, apoptosis, and proliferation were measured.
  
  
  RESULTS
  Fibroblasts derived from all 3 sites supported increased survival of CD4 T cells, mediated principally by interferon-beta. However, synovial and bone marrow fibroblasts shared an enhanced site-specific ability to maintain CD4 T cell survival in the absence of proliferation, an effect that was independent of fibroblast activation or proliferation but required direct T cell-fibroblast cell contact. In contrast, fibroblast-mediated neutrophil survival was less efficient, being independent of the site of origin of the fibroblast but dependent on prior fibroblast activation, and mediated solely by soluble factors, principally granulocyte-macrophage colony-stimulating factor.
  
  
  CONCLUSIONS
  These results suggest an important functional role for fibroblasts in the differential accumulation of leukocyte subsets in a variety of tissue microenvironments. The findings also provide a potential explanation for site-specific differences in the pattern of T cell and neutrophil accumulation observed in chronic inflammatory diseases.
authors.affiliation: MRC Centre for Immune Regulation, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Filer
authors.forename: Greg
authors.initials: G
authors.lastname: Parsonage
authors.forename: Emily
authors.initials: E
authors.lastname: Smith
authors.forename: Chloe
authors.initials: C
authors.lastname: Osborne
authors.forename: Andrew M C
authors.initials: AM
authors.lastname: Thomas
authors.forename: S John
authors.initials: SJ
authors.lastname: Curnow
authors.forename: G Ed
authors.initials: GE
authors.lastname: Rainger
authors.forename: Karim
authors.initials: K
authors.lastname: Raza
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Nash
authors.forename: Janet
authors.initials: J
authors.lastname: Lord
authors.forename: Mike
authors.initials: M
authors.lastname: Salmon
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Buckley
mesh_terms: D017209:Apoptosis / Q000502:physiology; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology*; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication / Q000502:physiology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D018920:Coculture Techniques; D016207:Cytokines / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000502:physiology; D006801:Humans; D016899:Interferon-beta / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D012867:Skin / Q000378:metabolism / Q000473:pathology; D013583:Synovial Membrane / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D005353:Fibronectins; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D016899:Interferon-beta; D016178:Granulocyte-Macrophage Colony-Stimulating Factor