Plasticity at the T cell receptor-peptide-major histocompatibility complex class I interface

Hopkins, Jade 2021. Plasticity at the T cell receptor-peptide-major histocompatibility complex class I interface. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Background – The interaction between the T cell receptor (TCR) on the surface of αβ T cells and the peptide-major histocompatibility complex (pMHC) on the surface of target cells helps αβ T cells to defend the host from virtually any foreign pathogen. To achieve such extensive coverage necessitates substantial T cell crossreactivity. While essential for providing complete immune coverage, T cell crossreactivity can also have negative consequences at it is believed to contribute to a large number of autoimmune diseases an can have fatal consequences when T cells are used therapeutically. The therapeutic deployment of the TCR-pMHC interaction therefore requires thorough understanding of the biochemical characteristics that underpin the interaction. Results – I began my studies by defining the crossreactive profile of an autoreactive T cell clone. Using combinatorial peptide library (CPL) screening, I showed that the HLA-A*0201- restricted, insulin-reactive InsB4 TCR, derived from a patient with type 1 diabetes (T1D) could be strongly activated by peptides arising from three common human pathogens. I further showed that EBV-insulin crossreactivity could be found in some T1D patients but not in healthy controls. The potential for virus-specific T cells to recognise self-antigens in autoimmune patients highlights the importance of understanding the underlying driving features of TCR plasticity. To this end, I set about investigating how two biochemical characteristics can influence the TCR-pMHC interaction, TCR sequence and pMHC flexibility. To explore how TCR sequence impacts TCR function, I profiled the crossreactive nature of an HLA-A*0201-restricted, HIV-1-specific TCR and compared its peptide recognition repertoire to mutant versions of the same TCR with CDR3 amino acid substitutions. These studies inadvertently resulted in the discovery that this TCR could also respond a self-antigen expressed on many HLA-A*0201+ cancer cell lines. Recognition of cancer cells, but not the cognate HIV-derived peptide, could be removed by a single CDR3 amino acid substitution. Finally, I studied how the dynamic flexibility of pMHC could be influenced by the peptide cargo by using red-edge excitation shift to examine a collection of well-studied analogues of a preproinsulin-derived peptide in the context of HLA A*0201. Conclusions – My research highlights both the negative (viral/autoimmunity) and the positive (viral/cancer) aspects of T cell crossreactivity and demonstrates that plasticity in both the TCR and cognate pMHC ligands are likely to play a role in the range of TCR-pMHC interactions that are capable of triggering a T cell response.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	4 May 2021
Last Modified:	04 Aug 2022 01:49
URI:	https://orca.cardiff.ac.uk/id/eprint/140916

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