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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:583108 |
| Date | January 2013 |
| Creators | Salim, Mahboob |
| Publisher | University of Birmingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://etheses.bham.ac.uk//id/eprint/4537/ |
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