Poster Presentation AUS-oMicS 2025

MR1 presents vitamin B6–related compounds for recognition by MR1-reactive T cells (119510)

Mitchell P McInerney 1 , Wael Awad 1 , Michael NT Souter 2 , Yang Kang 2 , Carl JH Wang 1 , Kean CY Poa 1 , Mohamed R Abdelaal 1 , Ngoc H Le 1 , Chloe M Shepherd 1 , Conor McNeice 1 , Adam G Nelson 2 , Lucy J Meehan 2 , Jeremy M Raynes 1 , Jeffrey YM Mak 3 , James McCluskey 2 , Zhenjun Chen 2 , Ching-Seng Ang 4 , David P Fairlie 3 , Jerome Le Nours 1 , Patricia T Illing 1 , Jamie Rossjohn 1 , Anthony W Purcell 1
  1. Department of Biochemistry and Molecular Biology and Immunity Program, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
  2. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
  3. Centre for Chemistry and Drug Discovery and Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
  4. Mass Spectrometry and Proteomics Facility, Bio21 Institute, The University of Melbourne, Melbourne, Victoria, Australia

T cells recognise and react to the presentation of foreign antigens displayed on the surface of all nucleated human cells. Peptide and lipid antigen presentation has dominated immunological research in this domain, but the lesser known MR1-mediated metabolite presentation system is emerging as an intriguing potential therapeutic target. MR1 was originally shown to present microbially derived vitamin B2 precursors to signal a localised infection to specialised T-cells, but evolutionary conservation of the MR1 gene indicates a broader purpose, prompting an expectation of many more ligands that mediate T-cell responses are waiting to be found. Using an unbiased mass spectrometry approach, here we identify pyridoxal (vitamin B6) as a naturally presented endogenous MR1 ligand, capable of activating the 7.G5 T-cell receptor, shown previously to recognise and kill cancer cells with high specificity. Subsequent metabolomic quantitation of pyridoxal and related vitamers in a panel of cancerous cells revealed vastly higher endogenous vitamin B6 levels compared to non-cancerous cell types, providing a potential mechanism for pyridoxal mediated cancer recognition by MR1-reactive T-cells.