The production of IFN-γ is important to control the growth of the opportunistic infection with Toxoplasma gondii. The ability of IL-12 to stimulate NK and T cells to produce IFN-γ is important for the development of resistance against T. gondii. IL-18, also called IGIF (Interferon-gamma inducing factor), is a cytokine which, like IL-12, can induce production of IFN-γ by NK and T cells, and is required for the development of optimal Th1 responses. To better understand the role of IL-18 in resistance to T. gondii, a variety of in vitro and in vivo assays were used to explore its role in activating innate and adaptive production of IFN-γ and its relationship with IL-12-mediated resistance. In vitro assays revealed an unexpected synergy between IL-18 and IL-10 to stimulate NK cell production of IFN-γ. However, this synergistic effect is only applicable to NK cells but not Th1 clones, and this difference between NK and T cells is associated with differential expression of the IL-10R. IL-10 is normally associated with inhibition of the production of IFN-γ but these findings add to our knowledge of the different cytokine combinations that can activate NK cells. Analysis of the role of IL-18 in resistance to T. gondii in SCID mice reveals that although IL-18 is produced in response to infection, endogenous IL-18 appears to have a limited contribution in the activation of innate resistance this parasite. Administration of exogenous IL-18 results in enhanced resistance to T. gondii, but these protective effects are largely dependent on endogenous IL-12. Similarly, studies with mice that lack IL-12-mediated signaling through STAT4 revealed that the development of protective T cell responses required for long-term resistance to T. gondii is dependent on this signaling pathway. However, treatment with IL-18, alone or in combination with IL-2, did not lead to the development of protective T cell responses, but did activate innate resistance independently of IL-12-mediated signaling. Together, these studies add to our understanding of the role of IL-18 in the events that lead to resistance to T. gondii
