Promiscuous recognition of MR1 drives self-reactive mucosal-associated invariant T cell responses

Andrew Chancellor, Robert Alan Simmons, Rahul C. Khanolkar, Vladimir Nosi, Aisha Beshirova, Giuliano Berloffa, Rodrigo Colombo, Vijaykumar Karuppiah, Johanne M. Pentier, Vanessa Tubb, Hemza Ghadbane, Richard J. Suckling, Keith Page, Rory M. Crean, Alessandro Vacchini, Corinne De Gregorio, Verena Schaefer, Daniel Constantin, Thomas Gligoris, Angharad LloydMiriam Hock, Velupillai Srikannathasan, Ross A. Robinson, Gurdyal S. Besra, Marc W. van der Kamp, Lucia Mori, Raffaele Calogero, David K. Cole, Gennaro De Libero, Marco Lepore

Research output: Contribution to journalArticlepeer-review

9 Citations (SciVal)

Abstract

Mucosal-associated invariant T (MAIT) cells use canonical semi-invariant T cell receptors (TCR) to recognize microbial riboflavin precursors displayed by the antigen-presenting molecule MR1. The extent of MAIT TCR crossreactivity toward physiological, microbially unrelated antigens remains underexplored. We describe MAIT TCRs endowed with MR1-dependent reactivity to tumor and healthy cells in the absence of microbial metabolites. MAIT cells bearing TCRs crossreactive toward self are rare but commonly found within healthy donors and display T-helper-like functions in vitro. Experiments with MR1-tetramers loaded with distinct ligands revealed significant crossreactivity among MAIT TCRs both ex vivo and upon in vitro expansion. A canonical MAIT TCR was selected on the basis of extremely promiscuous MR1 recognition. Structural and molecular dynamic analyses associated promiscuity to unique TCRβ-chain features that were enriched within self-reactive MAIT cells of healthy individuals. Thus, self-reactive recognition of MR1 represents a functionally relevant indication of MAIT TCR crossreactivity, suggesting a potentially broader role of MAIT cells in immune homeostasis and diseases, beyond microbial immunosurveillance.

Original languageEnglish
JournalThe Journal of Experimental Medicine
Volume220
Issue number9
DOIs
Publication statusPublished - 4 Sept 2023

Bibliographical note

RMC’s studentship is funded by the EPSRC. MWK is a BBSRC David Phillips Fellow (BB/M026280/1). This research made use of the Balena High Performance Computing (HPC) Service at the University of Bath.

Funding:
This work received funding from 875 the Swiss National Foundation 310030-173240 and 310030B-192828, Krebsliga BeiderBasel KLbB-4779-02-2019, Swiss Cancer League KFS-4707-02-2019, D-BSSE ETH Zürich PMB-877 02-17 (all to GDL), and from the University of Basel 3MM1055 to AC.

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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