瑞士巴塞尔大学Gennaro De Libero等研究人员合作发现，碳基核苷酸碱基加合物M₃Ade，是适应性多克隆MR1限制性T细胞的强大抗原。相关论文于2024年12月18日在线发表在《免疫》杂志上。

研究人员表示，主要组织相容性复合体（MHC）I类相关分子MHC类I相关蛋白1（MR1），向不同的MR1限制性T细胞亚群呈递代谢产物，包括黏膜相关不变T细胞（MAIT）和MR1T细胞。然而，自我反应性MR1T细胞及其识别的抗原性质尚未得到充分研究。

研究人员报道了一种细胞内源性的腺嘌呤碳基加合物（8-(9H-purin-6-yl)-2-oxa-8-azabicyclo[3.3.1]nona-3,6-diene-4,6-dicarbaldehyde [M3Ade]）被隔离在MR1的A'口袋中。M₃Ade在体外诱导了MR1介导的MR1T细胞克隆的刺激，这些克隆结合MR1-M₃Ade四聚体。

MR1-M₃Ade四聚体在健康供体、急性髓性白血病患者、以及非小细胞肺腺癌和肝细胞癌的肿瘤浸润淋巴细胞中，识别了异质性的MR1反应性T细胞。这些细胞在不同分化阶段显示出表型、转录组和功能上的多样性，表明其适应性特征。它们还是多克隆的，并且某些T细胞受体（TCRαβ）对使用有所偏好。

因此，M₃Ade是一个由MR1呈递的自我代谢产物，能够刺激和追踪来自血液和组织的人类MR1T细胞，有助于人们理解它们在健康和疾病中的作用。

附：英文原文

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

Author: 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 Hussinger, Timm Maier, Lucia Mori, Gennaro De Libero

Issue&Volume: 2024-12-18

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.

DOI: 10.1016/j.immuni.2024.11.019

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00534-X