How MR1 molecules present a novel family of antigens to MAIT cells
Major histocompatibility-related protein 1 (MR1) is an antigen presenting molecule which activates an abundant T cell subset in humans, called mucosal-associated invariant T (MAIT) cells. It has recently been found to present a completely novel type of antigen: small metabolites derived from the synthesis of Vitamin B by a wide range of pathogenic bacteria and yeast. After MR1 presents these antigens at the cell surface, MAIT cells become activated and initiate immune responses against the invading microbes.
We are pioneering the characterization of this new antigen presentation pathway. We showed that MR1 resides in the endoplasmic reticulum, where it captures Vitamin B antigens transported to this location by unknown mechanisms. MR1 is the only human antigen presenting molecule that behaves this way. Our major questions now are:
- How do the antigens reach the endoplasmic reticulum?;
- How is MR1 kept in an antigen-receptive conformation until the antigens reach its location?;
- How do the MR1-antign complexes traffic to the cell surface, and what is their fate?
To answer these questions we are using cutting-edge biochemical and molecular biology techniques such as CRISPR-Cas9 whole-genome screens, proteomics and confocal microscopy.
This project will unravel a novel mode to activate the immune system and reveal new approaches to harness the immune system against infections, autoimmunity and cancer.
Dr Hamish McWilliam
Professor Jose Villadangos
Professor David Fairlie (University of Queensland)
Professor Dale Godfrey (University of Melbourne)
Professor Jim McCluskey (University of Melbourne)
Dr Justine Mintern (University of Melbourne)
Professor Jamie Rossjohn (Monash University)
Professor Dick Strugnell ((University of Melbourne)
- Eckle SB, Birkinshaw RW, Kostenko L, Corbett AJ, McWilliam HE, Reantragoon R, Chen Z, Gherardin NA, Beddoe T, Liu L, Patel O, Meehan B, Fairlie DP, Villadangos JA, Godfrey DI, Kjer-Nielsen L, McCluskey J, Rossjohn J. A molecular basis underpinning the T cell receptor heterogeneity of mucosal-associated invariant T cells. J Exp Med 2014; 211: 1585-1600.
- McWilliam HE, Birkinshaw RW, Villadangos JA, McCluskey J, Rossjohn J. MR1 presentation of vitamin B-based metabolite ligands. Curr Opin Immunol 2015; 34: 28-34.
- McWilliam HE, Eckle SBG, Theodossis A, Liu L, Chen Z, Wubben JM, Fairlie DP, Strugnell RA, Mintern JD, McCluskey J, Rossjohn J, Villadangos JA. The intracellular pathway for the presentation of vitamin B-related antigens by the antigen-presenting molecule MR1. Nat Immunol 2016; 17: 531-537.
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