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Airway epithelial cell and macrophage regulation of pulmonary immunity

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Title: Airway epithelial cell and macrophage regulation of pulmonary immunity
Authors: Branchett, William Joseph
Item Type: Thesis or dissertation
Abstract: Regulation of pulmonary immunity is reliant on the sentinel function of airway macrophages (AM) and conducting airway epithelial cells. The aim of this thesis was to examine regulatory mechanisms utilised by AM and airway epithelial cells, focussing on the cytokines IL-10 and transforming growth factor beta1 (TGF-beta1). AM phenotype was examined in multiple models of pulmonary inflammation, establishing CD11b and MHC-II as robust AM activation markers. Transcriptomic analysis showed AM to increase expression of genes related to leukocyte recruitment, tissue repair, antigen presentation and metabolism by oxidative phosphorylation during allergic airway disease (AAD) driven by house dust mite (HDM) inhalation. However, AM also expressed genes encoding regulatory proteins such as TGF-beta1 and the retinoic acid-generating enzyme RALDH2 during AAD, suggesting that they retain immunoregulatory capacity even during established inflammation. AM were shown to produce minimal IL-10 in response to pro-inflammatory stimuli and AM-derived IL-10 was redundant for regulation of immune responses to inhaled allergen or respiratory syncytial virus infection. Conversely, T cell-specific IL-10 deletion enhanced the severity of HDMdriven AAD, accompanied by pulmonary heightened type 1 immunity and dysregulated AM activation, indicating that T cells are the dominant IL-10 producing cells in the allergic lung and may regulate AM activation via IL-10. Conditional knockout of TGF-beta1 in AM enhanced the type 2 immune response to HDM inhalation and increased production of the chemokine CCL2 by AM, suggesting a potential autocrine regulatory function of AM-derived TGF-beta1. Additionally, conducting airway epithelial club cells were shown to rapidly release TGF-beta1 into the airway lumen upon influenza infection. Conditional deletion of this TGF-beta1 source enhanced early interferon beta production to limit viral replication, suggesting that club cell-derived TGF-beta1 acts as a pro-viral factor during influenza infection. Collectively, these findings illustrate mechanisms by which immunoregulatory cytokines operate in context-specific niches during pulmonary inflammatory responses.
Content Version: Open Access
Issue Date: Dec-2017
Date Awarded: Mar-2018
URI: http://hdl.handle.net/10044/1/78573
DOI: https://doi.org/10.25560/78573
Copyright Statement: Creative Commons Attribution Non-Commercial No Derivatives licence.
Supervisor: Lloyd, Clare M.
Sponsor/Funder: Medical Research Council (Great Britain)
Asthma UK
Funder's Grant Number: 107059/Z/15/Z
Department: National Heart & Lung Institute
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:National Heart and Lung Institute PhD theses