T cell costimulation by fractalkine-expressing synoviocytes in rheumatoid arthritis

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.