Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

David Artis

Second Advisor

David M. Allman

Abstract

The barrier surfaces of the lung, intestine and skin are continually exposed to environmental insults, which can result in infection, inflammation and tissue injury when the barriers become disrupted. Epithelial barrier repair requires a balance between promoting beneficial remodeling responses that drive cell proliferation while also acting to limit these responses once homeostasis has been achieved. Failure to either initiate or resolve these reparative responses has detrimental effects, resulting in either loss of tissue integrity and function or promotion of chronic inflammation and fibrosis, as observed in multiple inflammatory diseases of the respiratory and intestinal tracts. While the immune system is integral to maintaining barrier integrity at these mucosal surfaces, the precise cellular and molecular factors that orchestrate restoration of homeostasis following tissue injury are poorly understood.

Over the past several years a novel family of immune cells have emerged called innate lymphoid cells (ILCs) that are crucial regulators of immunity and inflammation at barrier sites. However, whether ILCs exist in the respiratory tract and how they may influence immunity, inflammation or tissue homeostasis in the lung was unknown. The data presented in Chapter 2 identify a population of Group 2 ILCs (ILC2s) constitutively present in the respiratory tract of humans and mice and demonstrate a novel function for ILC2s in regulating airway epithelial barrier integrity and tissue homeostasis following influenza virus-induced pulmonary damage. Further, studies in Chapter 3 investigate the nature of the crosstalk between the damaged tissue and ILC2 function, revealing that ILC2s possess a wound healing transcriptional signature and identifying the amphiregulin (AREG)-epidermal growth factor receptor (EGFR) pathway as an essential regulator of airway epithelial repair and host recovery from influenza virus infection. Lastly, Chapter 4 explores the relevance of this pathway in sites outside the lung, uncovering an interleukin (IL)-33-dependent innate immune mechanism of intestinal tissue repair dependent on AREG-EGFR interactions. Collectively, the data presented in this thesis identify an evolutionarily conserved feedback loop in which cytokine cues from damaged epithelia activate innate immune cells to express growth factors essential for the restoration of epithelial function and maintenance of tissue homeostasis at multiple barrier surfaces.

Files over 3MB may be slow to open. For best results, right-click and select "save as..."

Included in

Biology Commons

Share

COinS