To clarify involvement of synovial T cells in the development of synovial inflammation in patients with rheumatoid arthritis (RA), we analyzed cellular interactions between synovial cells and infiltrating T cells via CD28/B7-1 and B7-2.
Synovial cells and infiltrating T cells were recovered separately from RA synovial tissues. Expression of CD28, B7-1, and B7-2 of synovial cells was analyzed by immunohistochemical staining and immunofluorescence analysis. Interleukin 1beta (IL-1beta), IL-6, and matrix metalloprotease 3 (MMP-3) secreted by synovial cells in the presence of infiltrating T cells were measured by ELISA. Nuclear transcription factor CD28 responsive complex was detected by a gel shift assay.
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+ cells were mainly LeuM3+ synovial cells. CD28 responsive complex was detected in nuclear extracts of freshly isolated lymphocytes from RA synovial tissues, but not those from osteoarthritis synovial tissues or normal peripheral blood, suggesting in vivo activation of T cells by the CD28/B7-1/B7-2 interactions. The irradiated autologous synovium infiltrating T cells notably enhanced IL-1beta, IL-6, and MMP-3 production by the synovial cells. The enhancement of proinflammatory cytokine and MMP-3 production by the synovial cells co-cultured with the T cells was abolished by the addition of CTLA4-Ig, anti-B7-1, and anti-B7-2 monoclonal antibodies.
These results suggest that cellular interactions between synovium infiltrating T lymphocytes and synovial cells via B7/CD28 pathways are intimately associated with development and exacerbation of inflammation in RA synovial cells.