Molecular basis underpinning MR1 allomorph recognition by an MR1-restricted T cell receptor

Molecular basis underpinning MR1 allomorph recognition by an MR1-restricted T cell receptor

IntroductionThe MHC-class-I-related molecule MR1 presents small metabolites of microbial and self-origin to T cells bearing semi-invariant or variant T cell receptors. One such T cell receptor, MC.7.G5, was previously shown to confer broad MR1-restricted reactivity to tumor cells but not normal cell...

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Main Authors: Richard J. Suckling, Cevriye Pamukcu, Robert Alan Simmons, Daniel Fonseca, Emma Grant, Rory Harrison, Saher A. Shaikh, Rahul C. Khanolkar, Hemza Ghadbane, Andrew Creese, Miriam Hock, Thomas G. Gligoris, Marco Lepore, Vijaykumar Karuppiah, Mariolina Salio
Format: Article
Language:English
Published: Frontiers Media S.A. 2025-03-01
Series:Frontiers in Immunology
Subjects:
MR1
cancer
metabolites
MAIT
TCR
Online Access:https://www.frontiersin.org/articles/10.3389/fimmu.2025.1547664/full
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Summary:IntroductionThe MHC-class-I-related molecule MR1 presents small metabolites of microbial and self-origin to T cells bearing semi-invariant or variant T cell receptors. One such T cell receptor, MC.7.G5, was previously shown to confer broad MR1-restricted reactivity to tumor cells but not normal cells, sparking interest in the development of non-MHC-restricted immunotherapy approaches.Methods/ResultsHere we provide cellular, biophysical, and crystallographic evidence that the MC.7.G5 TCR does not have pan-cancer specificity but is restricted to a rare allomorph of MR1, bearing the R9H mutation.DiscussionOur results underscore the importance of in-depth characterization of MR1-reactive TCRs against targets expressing the full repertoire of MR1 allomorphs.
ISSN:1664-3224

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