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- W2923453573 abstract "Abstract Toxoplasmic encephalitis is an AIDS-defining condition in HIV + individuals. The decline of IFN-γ-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-γ 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-γ production. Processing and secretion of IFN-γ-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. Author Summary A third of the world’s 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." @default.
- W2923453573 created "2019-04-01" @default.
- W2923453573 creator A5013841238 @default.
- W2923453573 creator A5021003953 @default.
- W2923453573 creator A5021131254 @default.
- W2923453573 creator A5027632335 @default.
- W2923453573 creator A5050019339 @default.
- W2923453573 creator A5072690991 @default.
- W2923453573 creator A5078417632 @default.
- W2923453573 creator A5083215979 @default.
- W2923453573 date "2019-03-29" @default.
- W2923453573 modified "2023-09-27" @default.
- W2923453573 title "Treatment of mice with IL2-complex enhances inflammasome-driven IFN-γ production and prevents lethal toxoplasmosis" @default.
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