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 Lloyd; Miriam 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

doi:10.1084/jem.20221939

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

Department of Psychology

Research output: Contribution to journal › Article › peer-review

21 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 language	English
Journal	The Journal of Experimental Medicine
Volume	220
Issue number	9
DOIs	https://doi.org/10.1084/jem.20221939
Publication status	Published - 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

Access to Document

10.1084/jem.20221939Licence: CC BY-NC-SA

https://research-information.bris.ac.uk/en/publications/promiscuous-recognition-of-mr1-drives-self-reactive-mucosal-assoc

Cite this

Chancellor, A., Alan Simmons, R., Khanolkar, R. C., Nosi, V., Beshirova, A., Berloffa, G., Colombo, R., Karuppiah, V., Pentier, J. M., Tubb, V., Ghadbane, H., Suckling, R. J., Page, K., Crean, R. M., Vacchini, A., De Gregorio, C., Schaefer, V., Constantin, D., Gligoris, T., ... Lepore, M. (2023). Promiscuous recognition of MR1 drives self-reactive mucosal-associated invariant T cell responses. The Journal of Experimental Medicine, 220(9). https://doi.org/10.1084/jem.20221939

Chancellor, A, Alan Simmons, R, Khanolkar, RC, Nosi, V, Beshirova, A, Berloffa, G, Colombo, R, Karuppiah, V, Pentier, JM, Tubb, V, Ghadbane, H, Suckling, RJ, Page, K, Crean, RM, Vacchini, A, De Gregorio, C, Schaefer, V, Constantin, D, Gligoris, T, Lloyd, A, Hock, M, Srikannathasan, V, Robinson, RA, Besra, GS, van der Kamp, MW, Mori, L, Calogero, R, Cole, DK, De Libero, G & Lepore, M 2023, 'Promiscuous recognition of MR1 drives self-reactive mucosal-associated invariant T cell responses', The Journal of Experimental Medicine, vol. 220, no. 9. https://doi.org/10.1084/jem.20221939

@article{c68c8f18e99f4a198d774784142f16e9,

title = "Promiscuous recognition of MR1 drives self-reactive mucosal-associated invariant T cell responses",

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.",

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

note = "RMC{\textquoteright}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 Z{\"u}rich PMB-877 02-17 (all to GDL), and from the University of Basel 3MM1055 to AC. ",

year = "2023",

month = sep,

day = "4",

doi = "10.1084/jem.20221939",

language = "English",

volume = "220",

journal = "The Journal of Experimental Medicine",

issn = "1540-9538",

publisher = "Rockefeller University Press",

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TY - JOUR

T1 - Promiscuous recognition of MR1 drives self-reactive mucosal-associated invariant T cell responses

AU - Chancellor, Andrew

AU - Alan Simmons, Robert

AU - Khanolkar, Rahul C.

AU - Nosi, Vladimir

AU - Beshirova, Aisha

AU - Berloffa, Giuliano

AU - Colombo, Rodrigo

AU - Karuppiah, Vijaykumar

AU - Pentier, Johanne M.

AU - Tubb, Vanessa

AU - Ghadbane, Hemza

AU - Suckling, Richard J.

AU - Page, Keith

AU - Crean, Rory M.

AU - Vacchini, Alessandro

AU - De Gregorio, Corinne

AU - Schaefer, Verena

AU - Constantin, Daniel

AU - Gligoris, Thomas

AU - Lloyd, Angharad

AU - Hock, Miriam

AU - Srikannathasan, Velupillai

AU - Robinson, Ross A.

AU - Besra, Gurdyal S.

AU - van der Kamp, Marc W.

AU - Mori, Lucia

AU - Calogero, Raffaele

AU - Cole, David K.

AU - De Libero, Gennaro

AU - Lepore, Marco

N1 - 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.

PY - 2023/9/4

Y1 - 2023/9/4

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85164233114

U2 - 10.1084/jem.20221939

DO - 10.1084/jem.20221939

M3 - Article

C2 - 37382893

AN - SCOPUS:85164233114

SN - 1540-9538

VL - 220

JO - The Journal of Experimental Medicine

JF - The Journal of Experimental Medicine

IS - 9

ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

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