Synovium infiltrating T cells induce excessive synovial cell function through CD28/B7 pathway in patients with rheumatoid arthritis

Objective. To clarify involvement of synovial T cells in the development of synovial inflammation in patients with rheumatoid arthritis (RA), we analy zed cellular interactions between synovial cells and infiltrating T cells v ia CD28/B7-1 and B7-2. Methods. Synovial cells and infiltrating T cells were recovered separately from RA synovial tissues. Expression of CD28, B7-1, and B7-2 of synovial ce lls was analyzed by immunohistochemical staining and immunofluorescence ana lysis. Interleukin 1 beta (IL-1 beta), IL-6, and matrix metalloprotease 3 ( MMP-3) secreted by synovial cells in the presence of infiltrating T cells w ere measured by ELISA. Nuclear transcription factor CD28 responsive complex was detected by a gel shift assay. Results. Both CD28+ T cells and B7-1/B7-2+ cells were found accumulating in the mononuclear cell infiltrate of RA synovial tissues and B7-1/B7-2+ cell s were mainly LeuM3+ synovial cells. CD28 responsive complex was detected i n nuclear extracts of freshly isolated lymphocytes from RA synovial tissues , but not those from osteoarthritis synovial tissues or normal peripheral b lood, suggesting in vivo activation of T cells by the CD28/B7-1/B7-2 intera ctions. The irradiated autologous synovium infiltrating T cells notably enh anced IL-1 beta, IL-6, and MMP-3 production by the synovial cells. The enha ncement of proinflammatory cytokine and MMP-3 production by the synovial ce lls co-cultured with the T cells was abolished by the addition of CTLA4-Ig, anti-B7-1, and anti-B7-2 monoclonal antibodies. Conclusion, These results suggest that cellular interactions between synovi um infiltrating T lymphocytes and synovial cells via B7/CD28 pathways are i ntimately associated with development and exacerbation of inflammation in R A synovial cells.