Immunity And Cell Signaling In The Host Response To Toxoplasma Gondii Infection
The immune response to an invading pathogen must be tightly regulated so as to combat the infection while avoiding immune-mediated pathologies. This requires the coordinated response of both innate and adaptive immunity, involving an array of cell types, including T cells, macrophages, and dendritic cells. While many studies have examined the general host immune response to infection, this thesis aimed to more clearly dissect the roles of the chemokine receptor CXCR3 and [beta]-catenin in the coordination of this complex response by T cells and dendritic cells, respectively. I show that CXCR3 expression is required on CD4+ T cells for efficient clearance of the protozoan parasite Toxoplasma gondii during the intestinal response to infection. In the absence of this receptor, impaired CD4+ T cell-dependent IFN-[gamma] renders intestinal inflammatory monocytes inactive, and mice succumb to intestine-restricted overgrowth of parasite. Tissue resident dendritic cells are the first immune cells to recognize foreign antigen and are crucial to the initiation of adaptive immunity. I show that differentiation of CD8[alpha]+ and related CD103+ tissue resident DC subsets is positively regulated by [beta]catenin signaling, a pathway normally associated with tumorigenesis. Constitutive [beta]catenin signaling in DC thus leads to susceptibility of mice to Toxoplasma gondii infection by excessively promoting proinflammatory DC subsets in dependence on interferon regulatory factor (IRF) 8 expression, resulting in hyperactivation of CD4+ T cells. Interestingly, I show that [beta]-catenin signaling in bone marrow-derived DC (BMDC) displays the reverse phenotype, whereby antigen-specific T cell activation and cytokine production are impaired by these DC. This finding underscores the phenotypic and genetic variation among different DC subsets and that [beta]-catenin has the capacity to promote both inflammatory and tolerant DC subsets depending on context. The data in this thesis provide novel insight into the mechanisms of immune cell trafficking, signaling, and differentiation, which ultimately lead to host protection against microbial insult.
Toxoplasma gondii; Immunity; Infection
Denkers, Eric Young
Wagner, Bettina; August, Avery
Ph.D. of Immunology
Doctor of Philosophy
dissertation or thesis