Molecular mechanisms controlling peptide selection for immune recognition (360G-Wellcome-219479_Z_19_Z)

Peptide presentation on MHC-I molecules is central to mounting effective antiviral and antitumoral immune responses. However, we currently lack full insight regarding how peptides are selected onto these extremely polymorphic molecules. Following our discovery that TAPBPR is an MHC-I peptide editor which shapes the final antigen repertoire displayed for immune recognition, we have recently identified that polymorphism in MHC-I significantly impact on their ability to be edited by TAPBPR. Our findings question the concept that all MHC-I molecules undergo peptide selection via a largely identical manner. Our overarching aim is to gain insight into how polymorphisms in MHC-I influence the mechanism by which they gain peptide. We will focusing on three aspects: What impact do polymorphisms in MHC-I and TAPBPR have on the molecular mechanism of peptide selection? What is the specific biological function of TAPBPR? Can further molecular dissection of the presentation pathway reveal new insight into MHC-I biology and novel therapeutic targets? This work will enable deeper insight into how peptides are selected onto MHC-I. It will help uncover why specific MHC-I alleles are associated with particular disease. Furthermore, it will help in the development our novel TAPBPR-based therapeutics and maximise their full potential in cancer immunotherapy.