Structural and biophysical characterisation of T-cell receptor cross-reactivity in health and disease

Wall, Aaron 2021. Structural and biophysical characterisation of T-cell receptor cross-reactivity in health and disease. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Background – T-cells are a crucial component of the adaptive immune system, responsible for host immunity to numerous pathogens. T-cells recognise pathogenic peptides presented on target cells via the T-cell receptor. To facilitate comprehensive immune coverage, T-cell receptors can ‘cross-react’ with multiple pathogenic peptides. However, T-cell crossreactivity has also been implicated in autoimmune disease, where recognition of a pathogenic epitope can trigger autoimmune recognition. While the biochemical mechanism governing T-cell cross-reactivity has been previously investigated, many of these studies involve non-clinically relevant T-cells. To understand the physiological consequences of Tcell cross-reactivity and its biochemical mechanisms, clinically relevant T-cells needed to be studied. Results – I have studied several T-cells which have been implicated in disease. The first, the ST8 T-cell, had previously been shown to cross-react with multiple tumour-associated antigens, resulting in a more potent T-cell response against tumour cells. I presented structural evidence that the ST8 T-cell receptor recognises these different peptide residues via conserved hotspot residues present on its target peptides. I also showed that this hotspot recognition was present in another cancer-specific T-cell, MEL5, which can recognise the same tumour-associated antigens as ST8. These findings demonstrate a new mechanism by which T-cells could respond to tumour cells, thus highlighting a clinical benefit to T-cell crossreactivity. To address the potential drawbacks of T-cell cross-reactivity I also studied several T-cells clones (4C6, InsB4, and NLV2D9) which have been implicated in type 1 diabetes. Using a combinatorial library screen, I identified multiple pathogenic epitopes that were recognised by 4C6 and InsB4 which may act as a pathogenic trigger. Structural data showed these T-cells also utilise hotspot recognition to achieve cross-reactivity between peptides,

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	18 January 2022
Last Modified:	04 Feb 2022 10:41
URI:	https://orca.cardiff.ac.uk/id/eprint/146504

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