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Title: Understanding the molecular basis of γδ T cell receptor ligand recognition in cellular stress surveillance
Author: Salim, Mahboob
ISNI:       0000 0004 2748 5423
Awarding Body: University of Birmingham
Current Institution: University of Birmingham
Date of Award: 2013
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γδ T-cells are unconventional lymphocytes hypothesised to act at the interface between innate and adaptive immunity. Emerging evidence indicates γδ T-cells play important, nonredundant roles in lymphoid stress surveillance during infection and tumourigenesis, and γδ T-cell-focussed immunotherapy trials suggest their potential exploitation in cancer immunotherapy. However, the molecular basis of γδ TCR/ligand recognition is poorly understood. In this thesis I first focussed on ligand recognition by the LES TCR, which is derived from a Vδ2-negative T-cell and mediates TCR-dependent recognition of CMVinfected cells and tumour cell lines by binding to Endothelial Protein C Receptor (EPCR). After producing LES TCR in a conformationally correct form, I used mutagenesis to map the LES TCR binding site on EPCR. Importantly, EPCR was recognised independently of bound lipid, suggesting it acts as a stress ligand rather than an antigen presenting molecule, and highlighting the importance of TCR-extrinsic factors in recognition. Secondly, I determined an NMR structure of Skint-1, a selecting ligand for mouse skin-resident DETC γδ T-cells that play important roles in immunoregulation and tumour immunosurveillance. This emphasised structural features unique to Skint-1, and suggested interaction with a separate ligand, such as the DETC TCR. Collectively, these studies improve understanding of γδ T-cell recognition.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC0254 Neoplasms. Tumors. Oncology (including Cancer)