Inhibition of T cell apoptosis in the rheumatoid synovium

Synovial T cells in rheumatoid arthritis are highly differentiated and express a phenotype suggesting susceptibility to apoptosis (CD45RB(dull), CD45RO(bright), Bcl-2(low), Bax(high), Fas(high)). However, no evidence of T cell apoptosis was found in synovial fluid from any of 28 patients studied. In contrast, synovial fluid from 10 patients with crystal arthritis showed substantial levels of T cell apoptosis. The failure of apoptosis was not an intrinsic property of rheumatoid synovial T cells, as they showed rapid spontaneous apoptosis on removal from the joint. Synovial T cells from rheumatoid arthritis and gout patients could be rescued from spontaneous apoptosis in vitro either by IL-2R gamma chain signaling cytokines (which upregulate Bcl-2 and Bcl-x(L)) or by interaction with synovial fibroblasts (which upregulates Bcl-x(L) but not Bcl-2). The phenotype of rheumatoid synovial T cells ex vivo (Bcl-2(low), Bcl-x(L)(high)) suggested a fibroblast-mediated mechanism in vivo. This was confirmed by in vitro culture of synovial T cells with fibroblasts which maintained the Bcl-X(L)(high) Bcl-2(low) phenotype. Synovial T cells from gout patients were Bcl-2(low) Bcl-x(L)(low) and showed clear evidence of apoptosis in vivo. Inhibition experiments suggested that an integrin-ligand interaction incorporating the Arg-Gly-Asp motif is involved in fibroblast-mediated synovial T cell survival. We propose that environmental blockade of cell death resulting from interaction with stromal cells is a major factor in the persistent T cell infiltration of chronically inflamed rheumatoid synovium.