Investigating the role of cytokine signalling in human T follicular helper cell differentiation and function
File(s)
Author(s)
Foster, William Stefan
Type
Thesis
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.
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.
Version
Open Access
Date Issued
2019-12
Date Awarded
2020-08
Copyright Statement
Creative Commons Attribution NonCommercial NoDerivatives Licence
Advisor
Harker, James
Lloyd, Clare
Sponsor
Biotechnology and Biological Sciences Research Council (Great Britain)
MedImmune Inc.
Grant Number
WHRLG01109
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)