AUTHOR=Suckling Richard J. , Pamukcu Cevriye , Simmons Robert Alan , Fonseca Daniel , Grant Emma , Harrison Rory , Shaikh Saher A. , Khanolkar Rahul C. , Ghadbane Hemza , Creese Andrew , Hock Miriam , Gligoris Thomas G. , Lepore Marco , Karuppiah Vijaykumar , Salio Mariolina 

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

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1547664

DOI=10.3389/fimmu.2025.1547664

ISSN=1664-3224

ABSTRACT=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.