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 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.
Sawai
Hirokazu
H
Emory University School of Medicine, Atlanta, Georgia, USA.
Park
Yong Wook
YW
Roberson
James
J
Imai
Toshio
T
Goronzy
Jörg J
JJ
Weyand
Cornelia M
CM
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*
C515538:CX3CL1 protein, human; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; D008565:Membrane Proteins