Immunity. 2024 Dec 11. pii: S1074-7613(24)00534-X. [Epub ahead of print]
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.
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