T cell costimulation by fractalkine-expressing synoviocytes in rheumatoid arthritis

Hirokazu Sawai, Yong Wook Park, James Roberson, Toshio Imai, Jörg J. Goronzy, Cornelia M. Weyand

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

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 CX3CR1, the receptor for the chemokine fractalkine (FKN). This study explored whether interactions between CX3CR1 and FKN are relevant for T cell functions in rheumatoid synovitis. Methods. FKN expression was examined by real-time polymerase chain reaction and immunohistochemistry. CX3CR1 expression on peripheral blood T cells was analyzed by flow cytometry. T cell activation was quantified by determining proliferative responses, interferon-γ (IFNγ) 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 CX3CR1 (P < 0.001). Such CD4+,CD28-,CX3CR1+ T cells strongly adhered to FLS, with soluble FKN blocking the interaction. FKN expressed on FLS costimulated T cell-activating signals and amplified proliferation, IFNγ production, and expulsion of cytoplasmic granules. Conclusion. Senescent CD4+ T cells that accumulate in rheumatoid arthritis aberrantly express CX3CR1. 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.

Original languageEnglish (US)
Pages (from-to)1392-1401
Number of pages10
JournalArthritis and rheumatism
Volume52
Issue number5
DOIs
StatePublished - May 2005

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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