Interleukin-15 (IL-15) is a proinflammatory cytokine that is overexpressed in rheumatoid arthritis (RA), a disease characterized by activation of monocytes/macrophages (MΦ), and by expansion of autoreactive CD4+ T cells. We hypothesized that IL-15 plays a major role for this expansion of CD4+ T cells and modulates the phenotype of monocytes/MΦ and their interaction with CD4+ T cells. Here, we show that IL-15 enhances the proliferation of CD4+ T cells from patients with RA in peripheral blood mononuclear cell cocultures. To further dissect the underlying mechanisms, we employed MΦ from IL-15-/- or IL-15 transgenic mice. These were induced to differentiate or were stimulated with IL-15. Here we show that addition of IL-15 during differentiation of MΦ (into 'IL-15MΦ') and overexpression of IL-15 by MΦ from IL-15tg mice leads to increased levels of major histocompatibility complex class II expression. This resulted in enhanced stimulation of antigen-specific CD4 + T cells in vitro and was accompanied by reduced messenger RNA expression in MΦ for immunosuppressive SOCS3. The proliferation rates of IL-15MΦ and IL-15tgMΦ were high, which was reflected by increased p27Kip1 and reduced p21Waf1 levels. In view of high serum and synovial levels of IL-15 in patients with RA, our data suggest the possibility that this excess IL-15 in RA may stimulate monocytes/MΦ to activate the characteristic autoreactive CD4+ T cells in RA. © 2008 Blackwell Publishing Ltd.