رسالة جامعية

Regulation of intestinal regulatory T cells by prostaglandin E₂

التفاصيل البيبلوغرافية
العنوان: Regulation of intestinal regulatory T cells by prostaglandin E₂
المؤلفون: Crittenden, Siobhan
المساهمون: Yao, Chengcan, Howie, Sarah, Anderton, Stephen
بيانات النشر: University of Edinburgh, 2018.
سنة النشر: 2018
المجموعة: University of Edinburgh
مصطلحات موضوعية: 616.9, Prostaglandin E2, Th17 cell development, immune inflammation, PGE2, inflammatory bowel disease, IFNAR deficiency
الوصف: Pathogenesis 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.
نوع الوثيقة: Electronic Thesis or Dissertation
اللغة: English
الوصول الحر: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.763958Test
رقم الانضمام: edsble.763958
قاعدة البيانات: British Library EThOS