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Investigating the role of cytokine signalling in human T follicular helper cell differentiation and function

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Title: Investigating the role of cytokine signalling in human T follicular helper cell differentiation and function
Authors: Foster, William Stefan
Item Type: Thesis or dissertation
Abstract: T follicular helper cells (TFH) are required for the generation of high affinity antibodies following immune challenge. TFH are also implicated in a wide range of clinical conditions, including autoimmunity, compromised immunity, cancer and have also been implicated within the context of human allergic disease. Many of these conditions occur as a result of dysregulated TFH differentiation or maintenance. Thus, this work has focussed on refining our understanding of the mechanisms by which human TFH are differentiated, are maintained, and perform effector function. Firstly, a dysregulation in TFH homeostasis within the tonsils of house dust mite (HDM) sensitised children is demonstrated. Within these children, TFH are more numerous as well as more functionally active; having heightened production capacity of IL-4, a cytokine well discussed within the context of allergic disease. This therefore implicates the tonsil as a site of allergic disease progression, and raises interesting questions about the nature of tonsillectomy as a potential preventative measure for atopy and asthma development. Furthermore, this work investigates the integrated cytokine signals required for human TFH differentiation, in which STAT3/4 signals from IL-6/IL-12 as well as SMAD2/3 signals from TGF-β and Activin A are required for induction of the core BCL6 transcriptional network. This work also explores how TCR mediated IL-2 signalling influences human TFH differentiation, being necessary for optimal proliferation but also negatively regulating TFH phenotype. Finally, this work explores the identity of T follicular cytotoxic cells, a recently identified CD8 subset which resemble TFH. This work confirms TFC analogues can co-opt the signals used for TFH differentiation yet demonstrates that TFCs are not negatively regulated by IL-2, which has potential implications for IL-2 as a therapy for patients with chronic viral infection or autoimmune disease. Collectively, this work provides new detail on the mechanisms behind human TFH formation, an understanding that will be of continued importance in an era of immunotherapies.
Content Version: Open Access
Issue Date: Dec-2019
Date Awarded: Aug-2020
URI: http://hdl.handle.net/10044/1/96199
DOI: https://doi.org/10.25560/96199
Copyright Statement: Creative Commons Attribution NonCommercial NoDerivatives Licence
Supervisor: Harker, James
Lloyd, Clare
Sponsor/Funder: Biotechnology and Biological Sciences Research Council (Great Britain)
MedImmune Inc.
Funder's Grant Number: WHRLG01109
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



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