dc.contributor.advisor |
Dunbar, R |
en |
dc.contributor.author |
Sargent, Ashly |
en |
dc.date.accessioned |
2020-03-31T01:23:55Z |
en |
dc.date.issued |
2020 |
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dc.identifier.uri |
http://hdl.handle.net/2292/50181 |
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dc.description |
Full Text is available to authenticated members of The University of Auckland only. |
en |
dc.description.abstract |
TGFβ is a signalling molecule with a myriad of effects in the normal physiology of immune regulation. TGFβ is widely implicated in the suppression of T lymphocyte effector function. Therefore, the high concentrations of TGFβ characteristic of the tumour microenvironment are frequently involved in the failure of immunotherapeutic treatments. Recently within the host lab, a tumour associated myeloid population has been identified with an increased ability to produce TGFβ. We sought to develop methods for thein vitro characterisation of TGFβ effects on T lymphocytes to better characterise the effects this population is likely mediating. We also set out to establish the expression of TGFβ receptor molecules on healthy human immune cell subsets. We found that in the absence of CD28 co-stimulation, TGFβ inhibits various T lymphocyte functions in vitro to varying extents. We found that TGFβ potently reduced T lymphocyte expression of perforin, granzyme B and IFN-γ while modestly impairing proliferation and caused increased expression of PD-1 in the absence of CD28 co-stimulation. We concluded from these results that the most efficient way of measuring the effects of TGFβ on T lymphocytes in vitro should be conducted in the absence of CD28 co-stimulation. These experimental protocols also allowed us to examine FoxP3 induced upon activation. We demonstrated that FoxP3 expression in human T lymphocytes is induced potently when activated in the presence of IL-2 but only minimally in the absence of IL-2. We also found that FoxP3 expression within activated human T lymphocytes correlates positively with the induction of BLIMP1 which correlated positively with IL-10 production. IL-10 caused resting T lymphocytes to upregulate TGFβRII. FoxP3 expression also correlated with expression of the TGFβ presenting protein LRRC32 in activated CD4+ T lymphocytes. However, in activated CD8+ T lymphocytes LRRC32 expression is independent of FoxP3. Therefore, human T lymphocyte activation can induce FoxP3 and BLIMP1, and can modulate TGFβ signalling via IL-10 inducing TGFβRII and induction of LRRC32. Finally, using a novel high-dimensional flow cytometry panel, we found that in healthy human PBMC the naïve CD8+ T lymphocyte population expresses higher levels of TGFβRII relative to other T lymphocyte populations. Collectively these findings aid our understanding of both the role of TGFβ and the transcription factors FoxP3 and BLIMP1 in human T lymphocyte biology. Additionally, we hope that these data may aid future studies in understanding the role of TGFβ for potential therapeutic interventions. |
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dc.publisher |
ResearchSpace@Auckland |
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dc.relation.ispartof |
Masters Thesis - University of Auckland |
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dc.relation.isreferencedby |
UoA99265294112602091 |
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dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
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dc.rights |
Restricted Item. Full Text is available to authenticated members of The University of Auckland only. |
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dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.rights.uri |
http://creativecommons.org/licenses/by-nc-sa/3.0/nz/ |
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dc.title |
Interactions of TGFß and FoxP3 in human T lymphocytes |
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dc.type |
Thesis |
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thesis.degree.discipline |
Biological Sciences |
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thesis.degree.grantor |
The University of Auckland |
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thesis.degree.level |
Masters |
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dc.rights.holder |
Copyright: The author |
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pubs.elements-id |
797140 |
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pubs.org-id |
Science |
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pubs.org-id |
Biological Sciences |
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pubs.record-created-at-source-date |
2020-03-31 |
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dc.identifier.wikidata |
Q112953697 |
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