Abstract
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 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. 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 3CR1, 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 CX 3CR1 and FKN. Conclusion. 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.
Original language | English (US) |
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Pages (from-to) | 3215-3225 |
Number of pages | 11 |
Journal | Arthritis and rheumatism |
Volume | 56 |
Issue number | 10 |
DOIs | |
State | Published - Oct 2007 |
ASJC Scopus subject areas
- Immunology and Allergy
- Rheumatology
- Immunology
- Pharmacology (medical)