An integration of cytokine pathways in the immune response to toxoplasmosis

This thesis explores factors involved in the development of a protective immune response following infection with the intracellular protozoan parasite, Toxoplasma gondii. This pathogen elicits a strong cell mediated immune response characterized by the IL-12 driven production of IFN-γ by NK and T cells. While IL-12 is integral to the development of protective immunity, other co-factors are involved in enhancing Th1 responses. The first part of this thesis assesses the contribution of the cytokine IL-23 to immunity and this was addressed in the context of IL-12 deficient mice. Following infection of IL-12p35−/− mice and IL-12p40−/− mice, the p35−/− mice display enhanced resistance, though they eventually succumb to toxoplasmosis. Recent studies reported that IL-12p40−/− mice also lack IL-23, a heterodimeric cytokine consisting of IL-12p40 and p19, thereby suggesting that the increased resistance observed in the p35−/− mice is due to a protective effect of IL-23. This hypothesis is supported by the observation that addition of exogenous IL-23 to p40−/− mice enhanced resistance to infection. However, infection of p19 −/− mice revealed IL-23 is not necessary for the development of protective T cell responses. Together these studies lead to the conclusion that IL-23 provides a limited role of resistance to toxoplasmosis in the absence of IL-12. The second part of this thesis examines the role of the transcription factor STAT1 in the regulation of the IFN-γ mediated control of T. gondii replication, and the development of T cell responses. It was found that STAT1 is necessary in the induction of anti-microbial effector mechanisms, but not necessary in the evolution of protective T cell responses. The last part of this thesis addresses the role of endogenous IL-15 in immunity to T. gondii. These studies revealed that though naive IL-15 −/− mice have decreased numbers of NK and CD8+ T cells, IL-15 is not necessary for infection-induced expansion of these cells. Furthermore, IL-15 is not required for the development of long-term protective immune responses. Overall, this thesis addresses the complex immune response elicited during toxoplasmosis with a focus on the relative contribution of co-factors which enhance immunity to T. gondii