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The CD8-mediated optimisation of the antigen specific T-cell response

Dockree, Tamsin 2017. The CD8-mediated optimisation of the antigen specific T-cell response. PhD Thesis, Cardiff University.
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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.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 12 June 2018
Last Modified: 05 Feb 2020 03:44

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