Bishop, Emma Louise 
ORCID: 0000-0002-3480-7764
(2023).
Interrogating a role for tumour necrosis factor alpha in CD4\(^+\) T cell metabolism in health and inflammatory disease.
University of Birmingham.
Ph.D.
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Bishop2023PhD.pdf
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Abstract
Upon activation, CD4\(^+\) T cells undergo substantial metabolic reprogramming to support clonal expansion and effector function, largely promoted by T cell receptor (TCR) and CD28 signalling. Whether T cell-derived inflammatory cytokines, such as tumour necrosis factor alpha (TNF-α), amplify this process is not well understood but could be pertinent in chronic inflammatory diseases, such as rheumatoid arthritis (RA), where abundant TNF-α expression and dysregulated CD4\(^+\) T cell metabolic phenotypes are present. TNF-α has been previously identified to act as a co-stimulatory signal upon T cell activation, increasing proliferation and cytokine production. Yet, whether TNF-α controls CD4\(^+\) T cell metabolism has not been interrogated. Here, it was shown that blocking T cell-derived TNF-α supressed the activation of naïve CD4\(^+\) T cells and impaired their upregulation of glycolysis, amino acid uptake, and mitochondrial oxidation of glutamine. Conversely, addition of TNF-α was able to increase glycolysis in these cells. Interrogation of downstream signalling pathways identified that TNF-α drives these changes not through NFκB, which is most commonly reported to be downstream of TNF-α, but through the PI3K/Akt/mTOR pathway. T cell-derived TNF-α signalling was also shown to be involved in driving inflammatory T helper (Th)1 and Th17 cell differentiation in a partially Akt-dependent manner, whilst little effect on regulatory T cell (Treg) differentiation was observed. Finally, to interrogate a role for this TNF-α/PI3K/Akt metabolic axis in chronic inflammatory disease, peripheral blood CD4\(^+\) T cells from RA patients and healthy controls were analysed by flow cytometry. RA CD4\(^+\) T cells exhibited higher levels of membrane-bound TNF-α, mitochondrial mass, and Akt phosphorylation. These data implicate TNF-α signalling via PI3K/Akt in the dysregulated metabolic phenotype of RA CD4\(^+\) T cells.
| Type of Work: | Thesis (Doctorates > Ph.D.) | ||||||||||||
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| Award Type: | Doctorates > Ph.D. | ||||||||||||
| Supervisor(s): |
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| Licence: | All rights reserved | ||||||||||||
| College/Faculty: | Colleges (2008 onwards) > College of Medical & Dental Sciences | ||||||||||||
| School or Department: | Institute of Immunology and Immunotherapy | ||||||||||||
| Funders: | Wellcome Trust | ||||||||||||
| Subjects: | Q Science > QH Natural history > QH301 Biology Q Science > QR Microbiology > QR180 Immunology |
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| URI: | http://etheses.bham.ac.uk/id/eprint/13651 |
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