The molecular basis underpinning the potency and specificity of MAIT cell antigens

Wael Awad, Geraldine J.M. Ler, Weijun Xu, Andrew N. Keller, Jeffrey Y.W. Mak, Xin Yi Lim, Ligong Liu, Sidonia B.G. Eckle, Jérôme Le Nours, James McCluskey, Alexandra J. Corbett, David P. Fairlie, Jamie Rossjohn

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Abstract

Mucosal-associated invariant T (MAIT) cells are activated by microbial riboflavin-based metabolite antigens when presented by MR1. How modifications to the potent antigen 5-OP-RU affect presentation by MR1 and MAIT cell activation remains unclear. Here we design 20 derivatives, termed altered metabolite ligands (AMLs), to dissect the impact of different antigen components on the human MAIT–MR1 axis. Analysis of 11 crystal structures of MAIT T cell antigen receptor (TCR)–MR1–AML ternary complexes, along with biochemical and functional assays, shows that MR1 cell-surface upregulation is influenced by ribityl and non-ribityl components of the ligand and the hydrophobicity of the MR1–AML interface. The polar ribityl chain of the AML strongly influences MAIT cell activation potency through dynamic compensatory interactions within a MAIT TCR–MR1–AML interaction triad. We define the basis by which the MAIT TCR can differentially recognize AMLs, thereby providing insight into MAIT cell antigen specificity and potency.

Original languageEnglish
Article numbers41590
Number of pages12
JournalNature Immunology
DOIs
Publication statusPublished - Apr 2020

Keywords

  • Antigen processing and presentation
  • cellular immunity
  • immunology
  • proteins
  • structural biology

Cite this

Awad, W., Ler, G. J. M., Xu, W., Keller, A. N., Mak, J. Y. W., Lim, X. Y., Liu, L., Eckle, S. B. G., Le Nours, J., McCluskey, J., Corbett, A. J., Fairlie, D. P., & Rossjohn, J. (2020). The molecular basis underpinning the potency and specificity of MAIT cell antigens. Nature Immunology, [s41590]. https://doi.org/10.1038/s41590-020-0616-6