Treatment of mice with IL2-complex enhances inflammasome-driven IFN-γ production and prevents lethal toxoplasmosis

Abstract

Toxoplasmic encephalitis is an AIDS-defining condition in HIV+ individuals. The decline of IFN-{gamma}-producing CD4+ T cells in AIDS is a major contributing factor in reactivation of quiescent Toxoplasma gondii to an actively replicating stage of infection. Hence, it is important to identify CD4-independent mechanisms to control acute T. gondii infection. Here we have investigated the targeted expansion and regulation of IFN-{gamma} production by CD8+ T cells, DN T cells and NK cells in response to T. gondii infection using IL-2 complex (IL2C) pre-treatment in an acute in vivo mouse model. Our results show that expansion of CD8+ T cells, DN T cells and NK cell by S4B6 IL2C treatment increases survival rates of mice infected with T. gondii and this increased survival is dependent on both IL-12- and IL-18-driven IFN-{gamma} production. Processing and secretion of IFN-{gamma}-inducing, bioactive IL-18 is dependent on the sensing of active parasite invasion by multiple redundant inflammasome sensors in multiple hematopoietic cell types but independent from T. gondii-derived dense granule (GRA) proteins. Our results provide evidence for a protective role of IL2C-mediated expansion of CD8+ T cells, DN T cells and NK cells in murine toxoplasmosis and may represent a promising adjunct therapy for acute toxoplasmosis.\n\nAuthor SummaryA third of the worlds population is chronically infected with the parasite Toxoplasma gondii. In most cases the infection is asymptomatic, but in individuals suffering from AIDS, reactivation of brain and muscle cysts containing T. gondii is a significant cause of death. The gradual decline of CD4 T cells, the hallmark of AIDS, is believed to be a major contributing factor in reactivation of T. gondii infection and the development of acute disease. In this study, we show that targeted expansion of non-CD4 immune cell subsets can prevent severe disease and premature death via increased availability of interferon gamma-producing immune cells. We also demonstrate that the upstream signaling molecule interleukin-18 is required for the protective immune response by non-CD4 cells and show that the sensing of active parasite invasion by danger recognition molecules is crucial. Our findings reveal that targeted cell expansion may be a promising therapy in toxoplasmosis and suggests that the development of novel intervention strategies targeting danger recognition pathways may be useful against toxoplasmosis, particularly in the context of AIDS.