Research Fellows Directory
Professor Timothy Elliott
University of Southampton
The processing and presentation of cellular antigens to cytotoxic T lymphocytes (CTL) lies at the heart of protective immune responses to infections and cancer, be they natural or induced by vaccination. Peptides are selected for presentation from a highly diverse pool of candidates – but the mechanism behind this is still largely unknown.
We are investigating the peptide selecting function of MHC I molecules in the early secretory pathway and their distinct peptide presenting function at the cell surface. We were the first to distinguish these two functions and with others we have shown that MHC I selector function is an intrinsic property of the MHC I molecule, that is dependent on protein dynamics or plasticity; and that MHC I alleles depend to varying extent on the ER-resident cofactor protein Tapasin to enhance selector function. How Tapasin influences MHC I plasticity is a focus in our lab.
The final enzyme of the antigen processing pathway also resides in the ER – Endoplasmic Reticulum Aminopeptidase-1 or ERAP1 which collaborates with tapasin to ensure that only peptides with sufficiently high affinity are selected by MHC I.
There is growing evidence that CTL are beneficial in natural immunity to tumours: most convincingly from the strong correlation between levels of tumour-infiltrating T cells (particularly CD8+) and better prognosis regardless of the treatment used. We are investigating how CTL specificity – which in turn depends on peptide selection by MHC I on the target cell– influences outcome in cancer and the likelihood of a positive response to immunotherapy.
Overall then, our work looks to improve the success of immunotherapy by exploiting knowledge of the mechanism of antigen processing and presentation to enhance tumour immunity and help tailor medical decisions, natural genetic variation in components of the antigen processing pathway that will help tailor the right treatment for each patient.