T cell receptor of Fas-sensitive T cells in rheumatoid synovium

Apoptosis is found in synoviocytes and CD3+ T cells in the synovium of patients with rheumatoid arthritis (RA). To analyze the pathogenesis of apoptosis in rheumatoid synovium, we examined the expression of Fas Ag, Fas ligand (Fas-L), and TCR on T cells susceptible to anti-Fas mAbs. Fas Ag is expressed on 40 to 60% of CD3+ T cells in the synovium as measured by immunohistochemical and flow cytometry methods. It was observed by the reverse transcription-PCR method that Fas-L is overexpressed on T cells infiltrating the rheumatoid synovium. These results suggest that apoptosis in RA synovium is mediated by the Fas/Fas-L pathway. PCR-single-strand conformation polymorphism clearly demonstrated that more than 50% of T cells that accumulate in synovium are removed by incubation with anti-Fas mAbs for 24 h in vitro, indicating that these cells are Fas sensitive. Junctional sequence analysis revealed several conserved amino acids motifs (ERxxxSMNTE, IAAEGLLG, QxEGxD, VPD, TLAGxYNEQ, EPSE, LTNxGEL, QGK, NIP, GLL, and KWT) in the CDR3 region of accumulated Fas-sensitive T cell clones, whereas these motifs were not detected in Fas-resistant clones. In conclusion, our findings support the notion that Fas-sensitive T cells in rheumatoid synovium are generated by Ag stimulation and recognize relatively limited T cell epitopes on autoantigens, suggesting that susceptibility to anti-Fas mAbs might be a selection marker for activated autoreactive T cells in RA.