Tumor necrosis factor-α occupies a central role in rheumatoid arthritis (RA) pathogenesis. We now report that Interleukin-15 (IL-15) can induce TNF-α production in RA through activation of synovial T cells. Peripheral blood (PB) T cells activated by IL-15 induced significant TNF-α 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-α production by synovial T cells. In contrast, IL-2 induced significantly lower TNF-α production in either cell-contact-dependent or direct culture, and IL-8 and MIP-1α were ineffective. Antibodies against C069, LFA-1 or ICAM-1 significantly inhibited the ability of T cells to activate macrophages by cell contact.