MR1 – a molecular alarm system that detects pathogen metabolites

Summary This project will characterize the MR1 antigen presentation system using CRISPR/Cas9 gene editing, biochemistry techniques, confocal microscopy, immunological assays and multiple pathogen infection models.

Project Details

The antigen-presenting molecule MR1 alerts the immune system when an intracellular bacterial infection is taking place. It does this by capturing metabolite by-products from bacteria and presenting them at the cell surface to activate a type of leukocyte called mucosal-associated invariant T (MAIT) cells.  MAIT cells then directly kill the infected cell or secrete inflammatory cytokines to initiate protective immunity.

We have shown that MR1 captures pathogen metabolites inside the endoplasmic reticulum of the infected cell, but we do not know how the metabolites get there. The mechanisms that keep MR1 in a “receptive” state in the endoplasmic reticulum and that control the intracellular trafficking on MR1-metabolite complexes inside the cells are also unknown.

This project will characterize the MR1 antigen presentation system using CRISPR/Cas9 gene editing, biochemistry techniques, confocal microscopy, immunological assays and multiple pathogen infection models. The outcomes may reveal novel therapies to harness the MR1-MAIT cell axis against infection.

Further reading: HEG McWilliam et al (2016) Nat. Immunol., 17: 531-539; HEG McWilliam and JA Villadangos (2017) Trends Immunol. 38:679; HEG McWilliam and JA Villadangos (2018) Curr Opin Immunol 52:108.