Drs. Sawai and Park contributed equally to this work.
Fractalkine mediates T cell–dependent proliferation of synovial fibroblasts in rheumatoid arthritis
Article first published online: 28 SEP 2007
Copyright © 2007 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 56, Issue 10, pages 3215–3225, October 2007
How to Cite
Sawai, H., Park, Y. W., He, X., Goronzy, J. J. and Weyand, C. M. (2007), Fractalkine mediates T cell–dependent proliferation of synovial fibroblasts in rheumatoid arthritis. Arthritis & Rheumatism, 56: 3215–3225. doi: 10.1002/art.22919
- Issue published online: 28 SEP 2007
- Article first published online: 28 SEP 2007
- Manuscript Accepted: 22 JUN 2007
- Manuscript Received: 12 DEC 2006
- NIH. Grant Numbers: R01-AR-42527, R01-AI-44142, R01-AR-41974, R01-AI-57266
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.
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 CX3CR1 was monitored by fluorescence-activated cell sorting. The induction of CX3CR1 and its ligand FKN in FLS was quantified by real-time polymerase chain reaction.
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 CX3CR1, a chemokine receptor expressed on both T cells and FLS. Anti-CX3CR1 antibodies inhibited T cell production of tumor necrosis factor α (TNFα) and suppressed FLS proliferation. TNFα amplified the expansion of FLS by enhancing their expression of CX3CR1 and FKN.
FKN–CX3CR1 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 CX3CR1. This growth-promotion loop is amplified by TNFα produced by CX3CR1-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.