title: T cell costimulation by fractalkine-expressing synoviocytes in rheumatoid arthritis.
abstract: OBJECTIVE
  Patients with rheumatoid arthritis (RA) accumulate prematurely aged T cells that have acquired a new profile of regulatory receptors. Many of the de novo-expressed receptors are typically found on natural killer cells, including CX(3)CR1, the receptor for the chemokine fractalkine (FKN). This study explored whether interactions between CX(3)CR1 and FKN are relevant for T cell functions in rheumatoid synovitis.
  
  
  METHODS
  FKN expression was examined by real-time polymerase chain reaction and immunohistochemistry. CX(3)CR1 expression on peripheral blood T cells was analyzed by flow cytometry. T cell activation was quantified by determining proliferative responses, interferon-gamma (IFNgamma) secretion, and granule release. Fibroblast-like synoviocyte (FLS)/T cell adhesion was measured by the retention of 5-carboxyfluorescein diacetate succinimidyl ester-labeled T cells on FLS monolayers.
  
  
  RESULTS
  FKN was expressed on cultured synovial fibroblasts and hyperplastic synoviocytes in the rheumatoid tissue. Among CD4+ T cells, only senescent CD28- T cells were positive for CX(3)CR1 (P < 0.001). Such CD4+,CD28-,CX(3)CR1+ T cells strongly adhered to FLS, with soluble FKN blocking the interaction. FKN expressed on FLS costimulated T cell-activating signals and amplified proliferation, IFNgamma production, and expulsion of cytoplasmic granules.
  
  
  CONCLUSIONS
  Senescent CD4+ T cells that accumulate in rheumatoid arthritis aberrantly express CX(3)CR1. FKN, which is membrane-anchored on synoviocytes, enhances CD4+ T cell adhesion, provides survival signals, and costimulates the production of proinflammatory cytokines as well as the release of granules. By virtue of their altered receptor profile, senescent CD4+ T cells receive strong stimulatory signals from nonprofessional antigen-presenting cells in the synovial microenvironment.
authors.affiliation: Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Sawai
authors.forename: Yong Wook
authors.initials: YW
authors.lastname: Park
authors.forename: James
authors.initials: J
authors.lastname: Roberson
authors.forename: Toshio
authors.initials: T
authors.lastname: Imai
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002448:Cell Adhesion; D002478:Cells, Cultured; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C / Q000096:biosynthesis / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000502:physiology*; D013583:Synovial Membrane / Q000166:cytology* / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: C515538:CX3CL1 protein, human; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; D008565:Membrane Proteins