Alterations to metabolic pathways, in particular post-translational modification, are a recognised hallmark of diseases such as autoimmunity, inflammation and cancer, and potentially provide a source of altered self antigens that can stimulate immune responses. Most notably, phosphorylated peptides have emerged as a group of tumour associated antigens which can be presented by MHC molecules and recognised by T-cells, and therefore represent promising candidates for future cancer immunotherapy strategies. However, how antigen phosphorylation impacts upon antigen presentation and recognition remains unclear. During this study I demonstrated that the phosphate moiety of phosphopeptides bearing the canonical P4 phosphorylation is more structurally diverse in its binding mode than previously thought. Strikingly, two epitopes exhibited a major conformational change upon addition of the phosphate moiety, effectively creating “conformational neoantigens”. This occurred through a similar mechanism for each epitope, whereby the presence of the phosphate moiety raised the position of the P4 Serine, allowing phosphate-mediated contacts with MHC residues and distorting the conformation of the central epitope region most critical for T- cell receptor recognition. Finally, I found that recognition of phosphopeptides can be both phosphate-dependent and epitope-specific at the level of the T-cell receptor. Therefore, this study shows that phosphorylation can have a profound and diverse effect on antigen binding, epitope identity and T-cell receptor recognition. In summary, my studies suggest that phosphopeptides are not only tumour associated but also highly antigenically distinct, establishing them as attractive candidates for cancer immunotherapy strategies.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:567803 |
| Date | January 2013 |
| Creators | Stones, Daniel Henry |
| Publisher | University of Birmingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://etheses.bham.ac.uk//id/eprint/4048/ |
Page generated in 0.0018 seconds