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.

中文翻译：

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羰基核碱基加合物 M3Ade 是一种有效的适应性多克隆 MR1 限制性 T 细胞抗原


主要组织相容性复合体 （MHC） I 类相关分子 MHC I 类相关蛋白 1 （MR1） 将代谢物呈递给不同的 MR1 限制性 T 细胞亚群，包括粘膜相关不变 T 细胞 （MAIT） 和 MR1T 细胞。然而，自反应性 MR1T 细胞和公认抗原的性质仍未得到充分探索。在这里，我们报道了腺嘌呤 （8-（9H-嘌呤-6-基）-2-氧杂-8-氮杂双环 [3.3.1]九烷-3,6-二烯-4,6-二甲醛 [M ₃ Ade]）的细胞内源性羰基加合物被隔离在 MR1 的 A′ 口袋中。M ₃ Ade 诱导体外 MR1 介导的对结合 MR1-M ₃ Ade 四聚体的 MR1T 细胞克隆的刺激。MR1-M ₃ Ade 四聚体在健康供体、急性髓性白血病个体以及非小细胞肺腺癌和肝癌的肿瘤浸润淋巴细胞中离体鉴定出异质性 MR1 反应性 T 细胞。这些细胞在不同的分化阶段表现出表型、转录和功能多样性，表明它们的适应性。它们也是多克隆的，有一些优先使用 T 细胞受体 （TCRαβ） 对。因此，M ₃ Ade 是一种 MR1 呈递的自身代谢物，能够刺激和追踪血液和组织中的人 MR1T 细胞，有助于我们了解它们在健康和疾病中的作用。