The carbonyl nucleobase adduct M₃Ade is a potent antigen for adaptive polyclonal MR1-restricted T cells

Andrew Chancellor¹, Daniel Constantin², Giuliano Berloffa², Qinmei Yang², Vladimir Nosi³, José Pedro Loureiro², Rodrigo Colombo², Roman P Jakob⁴, Daniel Joss⁵, Michael Pfeffer⁵, Giulia De Simone⁶, Aurelia Morabito⁶, Verena Schaefer², Alessandro Vacchini², Laura Brunelli⁶, Daniela Montagna⁷, Markus Heim⁸, Alfred Zippelius⁹, Enrico Davoli⁶, Daniel Häussinger⁵, Timm Maier⁴, Lucia Mori², Gennaro De Libero¹⁰

Affiliations

¹ Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland. Electronic address: andrew.chancellor@unibas.ch.
² Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.
³ Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland; Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
⁴ Biozentrum, University of Basel, 4056 Basel, Switzerland.
⁵ Department of Chemistry, University of Basel, 4056 Basel, Switzerland.
⁶ Department of Environmental Health Science, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, Italy.
⁷ Department of Sciences Clinic-Surgical, Diagnostic and Pediatric, University of Pavia and Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
⁸ Hepatology Laboratory, Department of Biomedicine, University of Basel and University Hospital Basel, 4031 Basel, Switzerland.
⁹ Cancer Immunology, Department of Biomedicine, University of Basel and University Hospital Basel, 4031 Basel, Switzerland.
¹⁰ Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland. Electronic address: gennaro.delibero@unibas.ch.

PMID: 39701104
DOI: 10.1016/j.immuni.2024.11.019

Free article

The carbonyl nucleobase adduct M₃Ade is a potent antigen for adaptive polyclonal MR1-restricted T cells

Andrew Chancellor et al. Immunity. 2025.

Free article

. 2025 Feb 11;58(2):431-447.e10.

doi: 10.1016/j.immuni.2024.11.019. Epub 2024 Dec 18.

Authors

Affiliations

¹ Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland. Electronic address: andrew.chancellor@unibas.ch.
² Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.
³ Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland; Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
⁴ Biozentrum, University of Basel, 4056 Basel, Switzerland.
⁵ Department of Chemistry, University of Basel, 4056 Basel, Switzerland.
⁶ Department of Environmental Health Science, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, Italy.
⁷ Department of Sciences Clinic-Surgical, Diagnostic and Pediatric, University of Pavia and Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
⁸ Hepatology Laboratory, Department of Biomedicine, University of Basel and University Hospital Basel, 4031 Basel, Switzerland.
⁹ Cancer Immunology, Department of Biomedicine, University of Basel and University Hospital Basel, 4031 Basel, Switzerland.
¹⁰ Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland. Electronic address: gennaro.delibero@unibas.ch.

PMID: 39701104
DOI: 10.1016/j.immuni.2024.11.019

Abstract

The major histocompatibility complex (MHC) class I-related molecule MHC-class-I-related protein 1 (MR1) presents metabolites to distinct MR1-restricted T cell subsets, including mucosal-associated invariant T (MAIT) and MR1T cells. However, self-reactive MR1T cells and the nature of recognized antigens remain underexplored. Here, we report a cell endogenous carbonyl adduct of adenine (8-(9H-purin-6-yl)-2-oxa-8-azabicyclo[3.3.1]nona-3,6-diene-4,6-dicarbaldehyde [M₃Ade]) sequestered in the A' pocket of MR1. M₃Ade induced in vitro MR1-mediated stimulation of MR1T cell clones that bound MR1-M₃Ade tetramers. MR1-M₃Ade tetramers identified heterogeneous MR1-reactive T cells ex vivo in healthy donors, individuals with acute myeloid leukemia, and tumor-infiltrating lymphocytes from non-small cell lung adenocarcinoma and hepatocarcinoma. These cells displayed phenotypic, transcriptional, and functional diversity at distinct differentiation stages, indicating their adaptive nature. They were also polyclonal, with some preferential T cell receptor (TCRαβ) pair usage. Thus, M₃Ade is an MR1-presented self-metabolite that enables stimulation and tracking of human-MR1T cells from blood and tissue, aiding our understanding of their roles in health and disease.

Keywords: MR1; MR1T cells; carbonyl nucleobase adduct; single-cell analysis.

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Conflict of interest statement

Declaration of interests A.C., Q.Y., A.V., L.M., and G.D.L. are inventors in pending patent applications (WO2018162563 and WO2021144475) submitted by the University of Basel related to MR1T-based cancer immunotherapy. Matterhorn Biosciences AG supported the G.D.L. laboratory via a sponsored research agreement with the University of Basel.

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The carbonyl nucleobase adduct M₃Ade is a potent antigen for adaptive polyclonal MR1-restricted T cells

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The carbonyl nucleobase adduct M₃Ade is a potent antigen for adaptive polyclonal MR1-restricted T cells

Authors

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Abstract

Conflict of interest statement

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Full Text Sources

Research Materials