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

The major histocompatibility complex class I related protein (MR1) presents microbially derived vitamin B2 precursors to mucosal-associated invariant T (MAIT) cells. MR1 can also present other metabolites to activate MR1-restricted T cells expressing more diverse T cell receptors (TCRs), some with anti-tumor reactivity. However, knowledge of the range of the antigen(s) that can activate diverse MR1-reactive T cells remains incomplete. Here, we identify pyridoxal (vitamin B6) as a naturally presented MR1 ligand using unbiased mass spectrometry analyses of MR1-bound metabolites. Pyridoxal, and the related compound, pyridoxal 5-phosphate bound to MR1 and enabled cell surface upregulation of wild type MR1*01 and MR1 expressing the Arg9His polymorphism associated with the MR1*04 allotype in a manner dependent on Lys43-mediated Schiff-base formation. Crystal structures of MR1*01 in complex with pyridoxal and pyridoxal 5-phosphate showed how these ligands were accommodated within the A-pocket of MR1. T cell lines transduced with the 7.G5 TCR, which has reported "pan-cancer" specificity, were specifically activated by pyridoxal presented by antigen-presenting cells expressing MR1*01 and MR1 allotypes bearing the less common Arg9His polymorphism. 7.G5 T cells also recognized, to a lesser extent, pyridoxal 5-phosphate and, importantly, recognition of both vitamers was blocked by an anti-MR1 antibody. 7.G5 TCR reactivity toward pyridoxal was enhanced when presented by the Arg9His polymorphism-bearing MR1 allotypes. Vitamin B6, and vitamers thereof, have been associated with various cancers, and here we describe a link between this ligand, MR1, and its allomorphs, and the pan-cancer 7.G5 TCR. This work identifies an MR1 ligand that can activate a diverse MR1-restricted TCR.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2024-11-26
DOI
https://doi.org/10.1073/pnas.2414792121
Citations
20
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
4.81

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article

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

Patricia T. Illing, Adam G. Nelson, James McCluskey, Jérôme Le Nours et al.
20 citations
Proceedings of the National Academy of Sciences
Immune Cell Function and Interaction
4.81
article

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

Patricia T. Illing, Adam G. Nelson, James McCluskey, Jérôme Le Nours, Wael Awad, Jeffrey Y. W. Mak, Mitchell P. McInerney, David P. Fairlie, Ching‐Seng Ang, Youngcheol Kang, Zhenjun Chen, Michael N. T. Souter, Mohamed R. Abdelaal, Jeremy M. Raynes, Lucy J. Meehan, Jamie Rossjohn, Anthony W. Purcell, Carl J. H. Wang, Kean Chan Yew Poa, Chloe M. Shepherd, Conor McNeice, Ngoc H. Le
article en
20 citations

Abstract

The major histocompatibility complex class I related protein (MR1) presents microbially derived vitamin B2 precursors to mucosal-associated invariant T (MAIT) cells. MR1 can also present other metabolites to activate MR1-restricted T cells expressing more diverse T cell receptors (TCRs), some with anti-tumor reactivity. However, knowledge of the range of the antigen(s) that can activate diverse MR1-reactive T cells remains incomplete. Here, we identify pyridoxal (vitamin B6) as a naturally presented MR1 ligand using unbiased mass spectrometry analyses of MR1-bound metabolites. Pyridoxal, and the related compound, pyridoxal 5-phosphate bound to MR1 and enabled cell surface upregulation of wild type MR1*01 and MR1 expressing the Arg9His polymorphism associated with the MR1*04 allotype in a manner dependent on Lys43-mediated Schiff-base formation. Crystal structures of MR1*01 in complex with pyridoxal and pyridoxal 5-phosphate showed how these ligands were accommodated within the A-pocket of MR1. T cell lines transduced with the 7.G5 TCR, which has reported "pan-cancer" specificity, were specifically activated by pyridoxal presented by antigen-presenting cells expressing MR1*01 and MR1 allotypes bearing the less common Arg9His polymorphism. 7.G5 T cells also recognized, to a lesser extent, pyridoxal 5-phosphate and, importantly, recognition of both vitamers was blocked by an anti-MR1 antibody. 7.G5 TCR reactivity toward pyridoxal was enhanced when presented by the Arg9His polymorphism-bearing MR1 allotypes. Vitamin B6, and vitamers thereof, have been associated with various cancers, and here we describe a link between this ligand, MR1, and its allomorphs, and the pan-cancer 7.G5 TCR. This work identifies an MR1 ligand that can activate a diverse MR1-restricted TCR.

Proceedings of the National Academy of SciencesVol. 121(49)
Australian Research Council (AU), The University of Queensland (AU), The University of Melbourne (AU), Australian Regenerative Medicine Institute (AU), Peter Doherty Institute (AU), ARC Centre of Excellence for Innovations in Peptide and Protein Science (AU), Monash University (AU), Cardiff University (GB)
Australian Nuclear Science and Technology Organisation, Australian Cancer Research Foundation, Australian Synchrotron, Monash University, National Institutes of Health, Medical Research Council, Australian Research Council, National Health and Medical Research Council
Good health and well-being
Openalex Percentile: Top 4%
Immune Cell Function and Interaction
4.81
DOIOpen Access PDFOpenAlex
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