Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Christopher A. Hunter

Abstract

One of the major challenges faced by the immune system involves mounting an inflammatory response to control pathogen growth while limiting immune-mediated damage to the host. In order to achieve this balance, responding immune cells need to detect signals from the environment and react appropriately by promoting or attenuating inflammation. Cells of the immune system employ an array of sensors to respond to environmental cues, such as nuclear hormone receptors, cytokine receptors, and Toll-like receptors. The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, provides immune cells with an additional means of detecting and responding to environmental signals to promote immunity. The work presented in this thesis examines the effects of AHR signaling during infection with the protozoan parasite Toxoplasma gondii, a medically significant pathogen that naturally infects mice. A variety of AHR ligands are produced by the host and the parasite during toxoplasmosis, which raised the question of whether AHR activity influences the immune response in this setting. Chapter 2 of this thesis describes a role for the AHR in promoting natural killer cell production of IL-10 in vitro and in vivo following infection. NK cells basally expressed the AHR and IL-12 stimulation increased AHR levels in these cells. Inhibition of the AHR led to impaired NK cell IL-10 production in vitro, and NK cells isolated from T. gondii-infected Ahr-/- mice had defective expression of IL-10. Chapter 3 demonstrates context-dependent roles for the AHR during oral and chronic toxoplasmosis. Orally infected Ahr-/- animals exhibited more severe weight loss and increased intestinal tissue pathology compared to wild-type mice, which was associated with CD4+ T cell hyperactivation. Chronically infected Ahr-/- mice developed elevated parasite burdens, but the CD4+ T cell responses in these animals were comparable to those in wild-type animals. Collectively these studies indicate that the AHR has multiple context dependent roles in the immune response to T. gondii.

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