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

Awad, Wael, Ler, Geraldine J. M., Xu, Weijun, Keller, Andrew N., Mak, Jeffrey Y. W., Lim, Xin Yi, Liu, Ligong, Eckle, Sidonia B. G., Le Nours, Jérôme, McCluskey, James, Corbett, Alexandra J., Fairlie, David P. and Rossjohn, Jamie 2020. The molecular basis underpinning the potency and specificity of MAIT cell antigens. Nature Immunology 21 (4) , pp. 400-411. 10.1038/s41590-020-0616-6

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Nature Publishing Group
ISSN: 1529-2908
Date of First Compliant Deposit: 1 April 2020
Date of Acceptance: 23 January 2020
Last Modified: 02 Apr 2020 09:45

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