Fractalkine mediates T cell-dependent proliferation of synovial fibroblasts in rheumatoid arthritis.
OBJECTIVE
In rheumatoid arthritis (RA), synovial fibroblasts proliferate excessively, eventually eroding bone and cartilage. The aim of this study was to examine the mechanisms through which CD4 T cells, the dominant lymphocyte population in patients with rheumatoid synovitis, regulate synoviocyte proliferation.


METHODS
Fibroblast-like synoviocyte (FLS) lines were established from rheumatoid synovium. CD4 T cells from patients with RA and age-matched control subjects were cultured on FLS monolayers. FLS proliferation was quantified by cytometry, using carboxyfluorescein succinimidyl ester staining or microscopic enumeration of PKH26-stained FLS. Surface expression of the fractalkine (FKN) receptor CX(3)CR1 was monitored by fluorescence-activated cell sorting. The induction of CX(3)CR1 and its ligand FKN in FLS was quantified by real-time polymerase chain reaction.


RESULTS
The proliferation of FLS was significantly increased in the presence of CD4 T cells from patients with RA compared with control T cells. CD4+,CD28- T cells were particularly effective in supporting FLS growth, inducing a 25-fold expansion compared with a 5-fold expansion induced by CD4+,CD28+ T cells. The growth-promoting activity of CD4+,CD28- T cells was mediated through CX(3)CR1, a chemokine receptor expressed on both T cells and FLS. Anti-CX(3)CR1 antibodies inhibited T cell production of tumor necrosis factor alpha (TNFalpha) and suppressed FLS proliferation. TNFalpha amplified the expansion of FLS by enhancing their expression of CX(3)CR1 and FKN.


CONCLUSIONS
FKN-CX(3)CR1 receptor-ligand interactions regulate FLS growth and FLS-dependent T cell function. FLS stimulate autocrine growth by releasing FKN and triggering the activity of their own CX(3)CR1. This growth-promotion loop is amplified by TNFalpha produced by CX(3)CR1-expressing T cells upon stimulation by FKN-expressing FLS. These data assign a critical role to FKN and its receptor in fibroblast proliferation and pannus formation in RA.
Sawai
Hirokazu
H
Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Park
Yong W
YW
He
Xiaowen
X
Goronzy
Jörg J
JJ
Weyand
Cornelia M
CM
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000503:physiopathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D000073883:CX3C Chemokine Receptor 1; D016022:Case-Control Studies; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D054428:Chemokine CX3CL1 / Q000096:biosynthesis* / Q000276:immunology; D005260:Female; D005347:Fibroblasts / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D054428:Chemokine CX3CL1; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha