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Title: The role of the CD8 co-receptor in CD8+ T-cell activation
Author: Clement, Mathew
ISNI:       0000 0004 2733 5302
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2013
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CD8+ T-cells are essential for the immune control of pathogens and the natural eradication of cancer. CD8+ T-cells also play a major role in the pathogenesis of autoimmunity and alloreactivity. CD8+ T-cells recognize short peptide fragments (8-13 amino acids) presented at the target cell surface bound to Major Histocompatability Class I (MHCI) molecules. Tcell antigen recognition is unique in nature because it involves the binding of a single ligand (peptide–MHC [pMHC]) by two receptors (TCR and CD8). The CD8 glycoprotein, which serves as the coreceptor on MHCI-restricted T-cells, acts to enhance the antigen sensitivity of T-cells by binding to a largely invariant region of MHCI at a site distinct from the TCR docking platform. CD8 has been shown to have multiple roles including enhancing effects on early T-cell activation events and also in controlling the level of T-cell cross-reactivity. The pMHCI/CD8 interaction is classified as having a very weak binding affinity and very fast kinetics. I discovered that this low solution binding affinity is essential in maintaining homeostasis as dramatically increasing the strength of this interaction resulted in total loss of T-cell specificity and activation independent of TCR engagement. This led me to examine the possibility that anti-CD8 antibodies could also bypass the normal requirements for T-cell activation. I identified one specific clonotype of antibody capable of this phenomenon but simultaneously discovered multiple effector phenotypes of other anti-CD8 antibodies. These included both enhancing and inhibitory effects on pMHCI tetramer binding and CD8+ T-cell activation. Subsequently, I explored the possibility of using these inhibitory anti-CD8 antibodies to block T-cell function in systems which are highly dependent on CD8 such as autoreactive CD8+ T-cells. I demonstrated that targeting CD8 can be used as a strategy to block autoreactive CD8+ T-cell activation in the absence of any effect on pathogen specific immunity. This highlights a novel therapeutic strategy that warrants further investigation. Finally, I demonstrated that CD8 can alter the functional avidity of a CD8+ T-cell for its agonists and act to re-arrange the relative potencies of each of its potential agonists, a novel “focussing mechanism” for CD8 in T cell activation. These results provide new insight to the biological role of CD8 in T-cells and even predict a novel mechanism for CD8 in controlling T-cell function. My results also highlight the potential of targeting CD8 for immunotherapeutic design in autoimmune disorders.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QP Physiology ; QR180 Immunology