The carbonyl nucleobase adduct M3Ade is a potent antigen for adaptive polyclonal MR1-restricted T cells
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 [M<sub>3</sub>Ade]) sequestered in the A' pocket of MR1. M<sub>3</sub>Ade induced in vitro MR1-mediated stimulation of MR1T cell clones that bound MR1-M<sub>3</sub>Ade tetramers. MR1-M<sub>3</sub>Ade 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, M<sub>3</sub>Ade 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.
Authors
- Giulia De Simone (ORCID: https://orcid.org/0000-0002-4894-3708)
- Laura Brunelli (ORCID: https://orcid.org/0000-0002-5465-9586)
- Verena Schaefer (ORCID: https://orcid.org/0000-0001-7507-5435)
- Gennaro De Libero (ORCID: https://orcid.org/0000-0003-0853-7868)
- Markus H. Heim (ORCID: https://orcid.org/0000-0002-7523-4894)
- Qinmei Yang
- Daniel Joss (ORCID: https://orcid.org/0000-0002-9101-4525)
- Roman P. Jakob (ORCID: https://orcid.org/0000-0002-6451-8656)
- José Pedro Loureiro (ORCID: https://orcid.org/0000-0002-1744-6135)
- Aurelia Morabito (ORCID: https://orcid.org/0000-0003-4961-8728)
- Lucia Mori (ORCID: https://orcid.org/0000-0002-5522-4648)
- Daniel Häußinger (ORCID: https://orcid.org/0000-0002-4798-0072)
- Giuliano Berloffa (ORCID: https://orcid.org/0000-0003-3152-9858)
- Alfred Zippelius (ORCID: https://orcid.org/0000-0003-1933-8178)
- Timm Maier (ORCID: https://orcid.org/0000-0002-7459-1363)
- Andrew Chancellor (ORCID: https://orcid.org/0000-0001-9658-4124)
- Vladimir Nosi (ORCID: https://orcid.org/0009-0007-3759-9116)
- Enrico Davoli (ORCID: https://orcid.org/0000-0003-0933-1351)
- Alessandro Vacchini (ORCID: https://orcid.org/0000-0001-5473-9693)
- Daniela Montagna (ORCID: https://orcid.org/0000-0002-1533-579X)
- Michael Pfeffer (ORCID: https://orcid.org/0000-0003-2752-5619)
- Rodrigo Colombo (ORCID: https://orcid.org/0009-0002-8641-6252)
- Daniel Constantin (ORCID: https://orcid.org/0000-0003-3896-6428)
Institutions
- University of Basel (CH)
- Mario Negri Institute for Pharmacological Research (IT)
- University of Pavia (IT)
- University Hospital of Basel (CH)
- Department of Biomedicine Basel (CH)
- Policlinico San Matteo Fondazione (IT)
Publication Details
- Journal
- Immunity
- Published
- 2024-12-18
- DOI
- https://doi.org/10.1016/j.immuni.2024.11.019
- Citations
- 16
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 3.85