The onset of acute psoriasis and the exacerbation of chronic psoriasis are often associated with a history of bacterial infection. We demonstrate that while only few scid/scid mice develop disease when CD4+ CD45Rb high T cells are transferred alone, coadministration of LPS plus IL-12 or staphylococcal enterotoxin B into scid/scid mice 1 day after CD4+ CD45Rb high T cell transfer greatly enhances disease penetrance and severity. Most importantly, the skin lesions induced by this method exhibit many of the histologic hallmarks observed in human psoriasis. Skin infiltrating CD4+ T cells were predominantly memory/effector cells (CD45Rb low) and exhibited a highly polarized Th1 phenotype. To test whether the development of pathogenic T cells was dependent on their production of IFN-γ, we transferred IFN-γ−/− CD4+ CD45Rb high T cells into scid/scid or into T, B and NK cell-deficient scid/beige mice. Surprisingly, the incidence of psoriasis was similar to scid/scid animals that received IFN-γ+/+ T cells, although acanthosis of the skin was attenuated. In contrast, the development of psoriasis was abolished if anti-IL-12 mAb was administered on day 7 and 35 after T cell transfer. Skin-derived IFN-γ−/− inflammatory cells, but not cells from anti-IL-12-treated animals, secreted substantial amounts of TNF-α, suggesting that the inflammatory effect of IFN-γ−/− T cells may be partly exerted by TNF-α and that the therapeutic effect of anti-IL-12 may depend on its ability to down-regulate both TNF-α and IFN-γ. Overall, these results suggest that IL-12, independently of IFN-γ, is able to induce pathogenic, inflammatory T cells that are able to induce psoriasiform lesions in mice.