Tumor necrosis factor-alpha occupies a central role in rheumatoid arthritis (RA) pathogenesis. We now report that interleukin-15 (IL-15) can induce TNF-alpha production in RA through activation of synovial T cells. Peripheral blood (PB) T cells activated by IL-15 induced significant TNF-alpha production by macrophages via a cell-contact-dependent mechanism. Freshly isolated RA synovial T cells possessed similar capability, and in vitro, IL-15 was necessary to maintain this activity. IL-15 also induced direct TNF-alpha production by synovial T cells. In contrast, IL-2 induced significantly lower TNF-alpha production in either cell-contact-dependent or direct culture, and IL-8 and MIP-1 alpha were ineffective. Antibodies against CD69, LFA-1 or ICAM-1 significantly inhibited the ability of T cells to activate macrophages by cell contact.