Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Christopher A. Hunter

Abstract

The IL-1 family member cytokines are among the most ancient cell-cell signaling pathways relevant to the immune system, and as they have co-evolved with their hosts’ increasingly complex lifestyles and longer lifespans, they have developed a correspondingly diverse range of roles in immunity. Although they all utilize conserved downstream signaling cascade (MyD88 and NF-B), and have some overlapping activities there are also distinct functions in different disease settings which indicate that these are not simply redundant factors. Indeed, it is now appreciated that differences in expression or patterns of release of the cytokines themselves and the presence of natural regulatory mechanisms that govern their activity are key to understanding their immuno-biology. As factors involved in the response to infectious threats, the IL-1 family members serve as amplifiers of immune pathways, and thereby enhanced control of infection. However, these responses can cause collateral tissue damage associated with inflammation and thus these cytokines can also induce or exacerbate pathology. The studies presented here focus on the IL-1 family members IL-18 and IL-33 and their shared ability to promote ILC and T cell responses associated with resistance to intracellular infections. Using a murine model of infection with Toxoplasma gondii, a natural host-pathogen system, combined with a variety of engineered cytokines, the data presented reveal new insights into the factors that dictate when and how these cytokines contribute to protective or pathological immunity to T. gondii.

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