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

Andrew Chancellor; Daniel Constantin; Giuliano Berloffa; Qinmei Yang; Vladimir Nosi; José Pedro Loureiro; Rodrigo Colombo; Roman P Jakob; Daniel Joss; Michael Pfeffer; Giulia De Simone; Aurelia Morabito; Verena Schaefer; Alessandro Vacchini; Laura Brunelli; Daniela Montagna; Markus Heim; Alfred Zippelius; Enrico Davoli; Daniel Häussinger; Timm Maier; Lucia Mori; Gennaro De Libero

doi:10.1016/j.immuni.2024.11.019

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

Immunity. 2024 Dec 11:S1074-7613(24)00534-X. doi: 10.1016/j.immuni.2024.11.019. Online ahead of print.

Authors

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: [email protected].
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: [email protected].

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.