The molecular mechanism of peptide editing by MHC I allomorphs and its relevance
Speaker: Professor Tim Elliot, University of Southampton
Antigen processing and presentation is the key pathway underpinning the natural or artificial induction of anti-tumour cytotoxic T lymphocytes (CTL) because it generates the ligands that activate them. These are short tumour-derived peptides presented by polymorphic MHC class I molecules. They are selected by a process of peptide editing involving several intracellular cofactors. MHC class I molecules are structurally dynamic and different MHC I allotypes have different dynamic signatures – which underpin the peptide editing process. We have captured these features in computational models which can be used as tools to investigate how peptide editing influences the repertoire of tumour derived peptides that are displayed by MHC I and how they dictate the specificity of CD8+ T cell responses to tumours.
A peptide filtering relation quantifies MHC class I peptide optimization. Dalchau N., Phillips A., Goldstein L.D., Howarth M., Cardelli L., Emmott S., Werner J.M., Elliott T.J. (2011) PLoS Comput Biol 7(10): e1002144
Selector function of MHC I molecules is determined by protein plasticity. Bailey A, Dalchau N, Carter R, Emmott S, Phillips A, Werner JM, Elliott T. (2015). Sci. Rep. 5, (14928) 1-15; doi: 10.1038/srep14928 (2015).
Direct evidence for conformational dynamics in Major Histocompatibility Complex class I molecules. Andy van Hateren, Malcolm Anderson, Alistair Bailey, Jörn M. Werner, Paul J. Skipp, Tim Elliott (2017) J Biol Chem. 2017 Dec 8;292(49):20255-20269.
A mechanistic model for predicting cell surface presentation of competing peptides by MHC class I. Denise Boulanger, Ruth C. Eccleston, Andrew Phillips, Peter V. Coveney, Neil Dalchau and Tim Elliott. (2018). Front.Immunol.10.3389 doi.org/10.3389/fimmu.2018.01538
Reviews and comment:
Protein Plasticity and Peptide Editing in the MHC I Antigen Processing Pathway. Elliott, T. & Van Hateren, A. (2018). Biochemistry. 10: 1021-1023
Recent advances in Major Histocompatibility Complex (MHC) class I antigen presentation: Plastic MHC molecules and TAPBPR-mediated quality control. van Hateren A, Bailey A and Elliott T. (2017). F1000 Research 2017, 6(F1000 Faculty Rev):158 (doi: 10.12688/f1000research.10474.1)