Phenotype and function of regulatory T cells in Th1- and Th2-mediated inflammatory diseases.
dc.contributor.advisor
Anderton, Stephen
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dc.contributor.advisor
O'Connor, Richard
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dc.contributor.author
Nowakowska, Dominika Joanna
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dc.contributor.sponsor
Wellcome Trust
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dc.date.accessioned
2015-11-19T15:39:24Z
dc.date.available
2015-11-19T15:39:24Z
dc.date.issued
2013-07-06
dc.description.abstract
Regulatory T cells (Treg) are critical to the maintenance of immune tolerance, partly by
controlling the unwanted activation of effector T cells (Teff) and thereby enhancing the
resolution of autoimmune and allergic inflammation. Recent data suggest that Treg can
specialize to better control different types of inflammation by using transcriptional
machinery which controls differentiation and function of Teff. This thesis addresses
questions related to the efficacious use of Treg, notably their ability to adopt distinct
phenotypic profiles under different inflammatory contexts and their need to recognize
antigen in the inflamed organ.
Two differentially mediated mouse disease models were used in this project, namely
Th1/Th17-mediated experimental autoimmune encephalomyelitis (EAE) as a model of
multiple sclerosis and Th2-mediated allergic airways inflammation (AAI) as a model of
asthma. A new model of rMOG-induced AAI was developed to specifically answer the
questions on the importance of cell phenotype versus antigen-reactivity for the effective
Treg-mediated suppression. It was demonstrated that Treg from the inflamed CNS in
EAE had an upregulated expression of Th1 master regulator T-bet and Th1-associated
chemokine receptor CXCR3, whereas Treg derived from the inflamed lung in AAI had
an increased expression of Th2 master regulator GATA-3, lacked expression of T-bet
and displayed decreased levels of CXCR3. This specialized and activated phenotype was
restricted to tissue-derived Treg. The importance of appropriate Treg phenotype for
effective suppression was suggested by the observed inability of CNS-derived Treg to
inhibit AAI. A different Treg subset, TGF-β-induced Treg (iTreg), was shown to express
high levels of T-bet and CXCR3, but not GATA-3 upon induction in vitro. iTreg
effectively suppressed both Th1 and Th2 types of inflammation and the antigenreactivity
was key to this.
This thesis demonstrates that Treg are capable of acquiring a distinct phenotype
corresponding with a CD4+ T cell response driving inflammatory disease and identifies
antigen-reactivity as key to the efficacious suppression of inflammation. It also
highlights substantial phenotypic differences between iTreg and naturally-occurring Treg
which could be associated with different modes of suppression.
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dc.identifier.uri
http://hdl.handle.net/1842/11779
dc.language.iso
en
dc.publisher
The University of Edinburgh
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dc.subject
autoimmunity
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dc.subject
allergic airways inflammation
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dc.subject
regulatory T cells
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dc.title
Phenotype and function of regulatory T cells in Th1- and Th2-mediated inflammatory diseases.
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dc.type
Thesis or Dissertation
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dc.type.qualificationlevel
Doctoral
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dc.type.qualificationname
PhD Doctor of Philosophy
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