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

IF 25.5 1区医学 Q1 IMMUNOLOGY Immunity Pub Date : 2024-12-18 DOI:10.1016/j.immuni.2024.11.019

Andrew Chancellor, Daniel Constantin, , 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, Gennaro De Libero

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引用次数: 0

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.

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来源期刊

Immunity 医学-免疫学

CiteScore

49.40

自引率

2.20%

发文量

205

审稿时长

6 months

期刊介绍： Immunity is a publication that focuses on publishing significant advancements in research related to immunology. We encourage the submission of studies that offer groundbreaking immunological discoveries, whether at the molecular, cellular, or whole organism level. Topics of interest encompass a wide range, such as cancer, infectious diseases, neuroimmunology, autoimmune diseases, allergies, mucosal immunity, metabolic diseases, and homeostasis.

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