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 - http://www.scopus.com/inward/record.url?scp=85164233114&partnerID=8YFLogxK
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 -