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Title: The CD8-mediated optimisation of the antigen specific T-cell response
Author: Dockree, Tamsin
ISNI:       0000 0004 7223 739X
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2017
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CD8+ T-cells target infected and dysregulated cells for deletion. Failure of this response can result in persistent challenge, such as cancer or chronic infection. CD8+ T-cells recognize peptides in the context of major histocompatibility complex class I (MHCI) molecules on the surface of host cells. The detection of T-cell antigens involves the binding of two receptors (TCR and CD8) to a single ligand (pMHCI). Individual TCRs cross-react with >106 different peptide antigens to ensure coverage of all possible pMHCI. As a result of this high level of T-cell crossreactivity the TCR/pMHCI interaction is usually suboptimal and significant scope exists in optimization for therapeutic benefit. The CD8 coreceptor enhances T-cell sensitivity through several mechanisms and has a potent ability to tune the antigen specific Tcell response. The pMHCI/CD8 interaction is characterised by very weak affinity. Increasing the strength of the pMHCI/CD8 interaction by 15-fold has been shown to result in complete loss of antigen specificity. In this thesis, I have shown that loss of antigen specificity occurs at a defined pMHCI/CD8 threshold (KD ~ 27 μM). This finding suggests that there is scope to increase the strength of the pMHCI/CD8 interaction for therapeutic benefit without non-specific CD8 T-cell activation. I demonstrated that increasing the strength of the pMHCI/CD8 interaction by engineering a point mutation into cell surface CD8 can result in improved T-cell antigen sensitivity. I have further classified the means by which CD8 can control Tcell crossreactivity and how altering the strength of the pMHCI/CD8 interaction can alter the focus of the TCR. And finally, I demonstrated that the level of CD8 expressed at the surface can have a dramatic effect on T-cell activation. Overall, I have demonstrated that cell surface CD8 can be engineered to enhance the therapeutic efficacy of adoptive T-cell transfer irrespective of antigen specificity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available