Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Gregory F. Sonnenberg

Second Advisor

David Artis

Abstract

The mammalian gastro-intestinal tract is colonized by trillions of beneficial commensal bacteria that are essential for promoting normal host physiology. While the majority of commensal bacteria are found in the intestinal lumen, many species have also adapted to colonize different anatomical locations in the intestine including the surface of intestinal epithelial cells (IECs) and the interior of gut-associated lymphoid tissues. Distinct tissue localization of commensal bacteria permits unique interactions between these microbes and the mammalian immune system and collectively influences intestinal immune cell homeostasis. Conversely, dysregulated localization of commensal bacteria can lead to inappropriate activation of the immune system and is associated with numerous chronic infectious, inflammatory and metabolic diseases. Therefore, regulatory mechanisms that control proper anatomical containment of commensal bacteria are essential to maintain tissue homeostasis and limit pathology. Although the roles of luminal and epithelial-associated commensal bacteria on immune cell homeostasis have been extensively studied, how lymphoid tissue-resident commensals (LRC) modulate host immune responses is not well understood. Data in Chapter 2 will describe interactions between a genetically related family of LRCs that can colonize dendritic cells and induces lymphoid tissue-specific immune responses. Further, Chapter 3 will provide evidence that LRC-induced immune responses are mutually beneficial for itself and the host. Specifically, LRC-induced interleukin (IL)-22 enhances its own microbial colonization and LRC-induced IL-10 limits tissue inflammation during intestinal injury.

Dysregulated anatomical localization of commensal bacteria during chronic inflammatory conditions is typically associated with extra-intestinal complications including anemia or dysregulated iron homeostasis. Results in Chapter 4 support a role for the iron-regulatory hormone hepcidin in modulating LRC colonization of DCs and identify hepcidin as a critical regulator of immune cell homeostasis and tissue repair following intestinal injury. Collectively, studies presented in this thesis define mutually beneficial interactions between mammalian hosts and commensal bacteria in intestinal-associated lymphoid tissues that regulate immune cell homeostasis and host responses to tissue inflammation or injury.

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