Completed Infection & Immunity Cancer

Molecular mechanisms controlling peptide selection for immune recognition

Funder Wellcome Charity-funded
Recipient organisation University of Cambridge
Funding £1.9M
Period Apr 2020 — Apr 2025

In plain English

AI plain-English summary

Every person’s immune system uses a set of highly variable molecules called MHC-I to display fragments of viruses or tumours on cell surfaces, flagging them for destruction. But exactly how those fragments—peptides—are selected and loaded onto different MHC-I versions has remained unclear. The problem matters because certain MHC-I variants are linked to stronger or weaker immune responses against infections and cancers, yet the underlying molecular reasons are unknown. This research will dissect the role of a protein called TAPBPR, which the team discovered acts as an editor, trimming and swapping peptides on MHC-I. They will investigate how natural genetic variation in both MHC-I and TAPBPR changes the editing process. If successful, the work could explain why some people’s immune systems handle certain diseases better than others. More concretely, the team is already developing TAPBPR-based cancer immunotherapies, and understanding the editing mechanism at a molecular level would help optimise those treatments for maximum effectiveness. This is fundamental science with a clear translational path: deeper knowledge of peptide selection directly informs the design of therapies that rely on presenting the right antigens to immune cells.

View original technical description
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.

View the original record at the funder ↗

Researchers

Geoffrey Smith (EPMC Awardee)Louise Boyle (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Peptide selection in the MHC I antigen processing pathway and its relevance to cancer
MHC-I antigen processing and presentation in viral immune detection and evasion
Peptide editing in the MHC I antigen processing pathway and its relevance to cancer
A multi-level study of peptide editing in the MHC class I antigen processing pathway and its immunological consequences
Manipulation of a novel antigen presentation checkpoint to enhance the repertoire of tumour antigens presented for immune recognition

Original classification

Senior Research Fellowship Renewal

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.