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Novel unconventional T-cells in response to bacteria and cancer

Crowther, Michael 2018. Novel unconventional T-cells in response to bacteria and cancer. PhD Thesis, Cardiff University.
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Conventional T-cells respond to peptide antigens presented by person-specific Human Leukocyte Antigens (HLAs) and therefore therapies that harness such cells may only be applicable to a minority of individuals. Unconventional T-cells could bypass this limitation to provide an opportunity for population-wide disease treatments. Exploitation of such T-cells first requires a detailed study of the unconventional T-cells involved in the immune response. I therefore sought to characterise novel invariant T-cells generated in response to varied disease agents. Results – An optimised protocol for procurement of disease-relevant unconventional T-cells was established and used to generate T-cell lines and clones of interest. T-cell receptor (TCR) sequencing of unconventional T-cell populations revealed a predominance of mucosal-associated invariant cells and Vγ9Vδ2 T-cells. Enrichments for other shared TCR clonotypes included TRAV21 and TRAV13-1 genes, which have some evidence of an invariant nature. I identified an interesting T-cell clone that was capable of recognising a broad range of target cells through a novel mechanism. The ligand recognised by these T-cells was identified using a whole genome CRISPR approach. Further studies confirmed the nature of the ligand and that recognition was dependent on a new subtype of TCR that was present in all donors tested. Conclusions - The field of unconventional T-cells is rapidly expanding, with novel invariant T-cells proving to be a much greater part of the T-cell repertoire than previously estimated. New and undiscovered invariant T-cell subsets are likely to provide exciting novel immunotherapies and bypass the limitation of HLA-restriction that is associated with conventional T-cell recognition of peptide-major histocompatibility complex ligands.

Item Type: Thesis (PhD)
Date Type: Submission
Status: Unpublished
Schools: Medicine
Funders: Health and Care Research Wales
Date of First Compliant Deposit: 6 March 2020
Last Modified: 11 Dec 2020 03:21

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