A molecular basis underpinning TRBV28+ T cell receptor recognition of MR1-antigen

Awad, Wael, Gherardin, Nicholas A., Ciacchi, Lisa, Keller, Andrew N., Liu, Ligong, Fairlie, David P., McCluskey, James, Godfrey, Dale I. and Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522 2025. A molecular basis underpinning TRBV28+ T cell receptor recognition of MR1-antigen. Journal of Biological Chemistry , 110416. 10.1016/j.jbc.2025.110416

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Abstract

Mucosal-associated invariant T (MAIT) cells express a TRAV1-2+ T cell receptor (TCR) that recognises microbial vitamin B2-derivatives presented by the MHC class I-related molecule, MR1. Most MAIT TCRs incorporate a biased TCR-β repertoire, predominantly TRBV20-1 and TRBV6, but some utilise other TRBV genes, including TRBV28. A second conserved, albeit less frequent TRAV36+ TRBV28+ T cell population exhibits MAIT-like phenotypic features but use a markedly distinct mode of MR1-antigen-recognition compared to MAIT TCR-MR1 binding. Nevertheless, our understanding of how differing TCR gene usage results in altered MR1 binding modes remains incomplete. Here, binding studies demonstrated differential affinities and antigen-specificities between TRBV6+ and TRBV28+ MR1-restricted TCRs. Alanine-scanning mutagenesis on the TRAV36-TRBV28 TCR, revealed a strong dependence on germline-encoded residues within the highly selected CDR3α loop, similar to TRAV1-2- TRBV6 TCRs, and further alanine-scanning mutagenesis experiments demonstrate differential energetic footprints by these TCRs atop MR1. We determined the crystal structure of a MAIT TRAV1-2-TRBV28+ TCR-MR1-5-OP-RU ternary complex. This structure revealed a docking mode conserved amongst other TRAV1-2+ MAIT TCRs, with the TRBV28-encoded TCR-β chain adopting highly distinct docking modes between the TRAV1-2+ and TRAV36+ TCRs. This indicates that the TCR-α chain dictates the positioning and role of the TCR-β chain. Taken together, these findings provide new molecular insights into MR1-Ag driven selection of paired TCR-α and TCR-β chains.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Publisher:	Elsevier
ISSN:	0021-9258
Date of First Compliant Deposit:	1 July 2025
Date of Acceptance:	20 June 2025
Last Modified:	01 Jul 2025 11:45
URI:	https://orca.cardiff.ac.uk/id/eprint/179410

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