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dc.contributor.advisorYao, Chengcan
dc.contributor.advisorHowie, Sarah
dc.contributor.advisorAnderton, Stephen
dc.contributor.authorCrittenden, Siobhan
dc.date.accessioned2018-10-18T09:30:16Z
dc.date.available2018-10-18T09:30:16Z
dc.date.issued2018-11-30
dc.identifier.urihttp://hdl.handle.net/1842/33140
dc.description.abstractPathogenesis of autoimmune and auto-inflammatory diseases is induced by auto-aggressive helper T (Th) cells (i.e. Th1 and Th17 cells), and can be controlled by regulatory T cells (Tregs) characterized by expression of the transcription factor Foxp3. Thus, development of autoimmunity is regulated by the balance of Tregs and Th1/Th17 cells. Prostaglandin E₂ (PGE₂) is a bioactive lipid mediator with immune-modulatory potential that acts through 4 receptors (EP1-4). It has been shown that PGE₂ facilitates Th1 and Th17 cell development and expansion, therefore promoting autoimmune inflammation. However, the role of PGE₂ in Treg development and function is largely unclear. The aim of this PhD was to test the hypothesis that PGE₂ regulates Treg development, function and subsequent immune response. I observed that in vivo inhibition of endogenous PGE₂ biosynthesis using a COX inhibitor resulted in increased Foxp3+ Tregs in various lymphoid organs. This response was prevented by addition of an EP4 agonist. PGE₂-EP4 signalling particularly inhibits RORγt+ Tregs in the intestine. This was not observed in either antibiotic-treated mice or MyD88/TRIF double-knockout mice, suggesting gut commensal microbiota involvement. In addition, PGE₂ has a role in microbiota-dependent regulation of intestinal CD11c+MHCII+CD11b+CD103- mononuclear phagocytes (MNPs) which drive intestinal Treg expansion through production of type 1 interferons. Consistent with these in vivo observations, gut microbial metabolites from indomethacin treated mice enhanced in vitro RORγt+ Treg differentiation in the dendritic cell- T cell co-culture system. Adoptive transfer of caecal microbiota from COX inhibitor- treated mice into naïve mice also provided protective benefits in a chemical (DSS)-induced colitis disease model. In summary, this work has demonstrated that PGE₂ affects intestinal Tregs, indicating a novel mechanism for interaction of PGE₂, the adaptive immune system and the gut microbiota in homeostasis within this environment. These findings increase our understanding of the role of PGE₂ in development of inflammatory bowel disease and offer potential therapeutic strategies for treating this disease.en
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversionDuffin, R., et al., Prostaglandin E(2) constrains systemic inflammation through an innate lymphoid cell-IL-22 axis. Science, 2016. 351(6279): p. 1333-8.en
dc.relation.hasversionRobb, C.T., et al., Prostaglandin E2 stimulates adaptive IL-22 production and promotes allergic contact dermatitis. J Allergy Clin Immunol, 2017.en
dc.relation.hasversionFelton, J.M., et al., Facilitation of IL-22 production from innate lymphoid cells by prostaglandin E. Thorax, 2018.en
dc.subjectProstaglandin E₂en
dc.subjectTh17 cell developmenten
dc.subjectimmune inflammationen
dc.subjectPGE₂en
dc.subjectinflammatory bowel diseaseen
dc.subjectIFNAR deficiencyen
dc.titleRegulation of intestinal regulatory T cells by prostaglandin E₂en
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dc.rights.embargodate2019-11-30en
dcterms.accessRightsRestricted Accessen


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