MR1-restricted T (MR1T) cells are defined by their recognition of metabolite antigens presented by the monomorphic MHC class 1-related molecule, MR1, the most highly conserved MHC class I related molecule in mammalian species. Mucosal-associated invariant T (MAIT) cells are the predominant subset of MR1T cells expressing an invariant TCR alpha-chain, TRAV1-2. These cells comprise a T cell subset that recognizes and mediates host immune responses to a broad array of microbial pathogens, including Mycobacterium tuberculosis. Here, we sought to characterize development of circulating human MR1T cells as defined by MR1-5-OP-RU tetramer labelling and of the TRAV1-2+ MAIT cells defined by expression of TRAV1-2 and high expression of CD26 and CD161 (TRAV1-2+CD161++CD26++ cells). We analysed postnatal expansion, maturation and functionality of peripheral blood MR1-5-OP-RU tetramer+ MR1T cells in cohorts from three different geographic settings with different tuberculosis (TB) vaccination practices, levels of exposure to and infection with M. tuberculosis. Early after birth, frequencies of MR1-5-OP-RU tetramer+ MR1T cells increased rapidly by several fold. This coincided with the transition from a predominantly CD4+ and TRAV1-2- population in neonates, to a predominantly TRAV1-2+CD161++CD26++ CD8+ population. We also observed that tetramer+ MR1T cells that expressed TNF upon mycobacterial stimulation were very low in neonates, but increased ~10-fold in the first year of life. These functional MR1T cells in all age groups were MR1-5-OP-RU tetramer+TRAV1-2+ and highly expressed CD161 and CD26, markers that appeared to signal phenotypic and functional maturation of this cell subset. This age-associated maturation was also marked by the loss of naive T cell markers on tetramer+ TRAV1-2+ MR1T cells more rapidly than tetramer+TRAV1-2- MR1T cells and non-MR1T cells. These data suggest that neonates have infrequent populations of MR1T cells with diverse phenotypic attributes; and that exposure to the environment rapidly and preferentially expands the MR1-5-OP-RU tetramer+TRAV1-2+ population of MR1T cells, which becomes the predominant population of functional MR1T cells early during childhood.

中文翻译：

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人类MR1 T细胞的产后扩增，成熟和功能

MR1限制性T（MR1T）细胞的定义是，它们识别由MHC 1类单态相关分子MR1呈现的代谢物抗原，MR1是哺乳动物物种中最保守的I类MHC相关分子。粘膜相关不变T（MAIT）细胞是表达不变TCRα链TRAV1-2的MR1T细胞的主要子集。这些细胞包含一个T细胞亚群，可识别并介导宿主对多种微生物病原体（包括结核分枝杆菌）的免疫反应。在这里，我们试图表征由MR1-5-OP-RU四聚体标记定义的循环人类MR1T细胞和由TRAV1-2的表达以及CD26和CD161（TRAV1的高表达）定义的TRAV1-2 + MAIT细胞的发育。 2 + CD161 ++ CD26 ++个单元格）。我们分析了产后扩张，来自三个不同地理环境的人群的外周血MR1-5-OP-RU四聚体+ MR1T细胞的成熟度和功能，其接种方法不同，结核分枝杆菌的暴露水平和感染水平。出生后早期，MR1-5-OP-RU四聚体+ MR1T细胞的频率迅速增加了几倍。这与新生儿中以CD4 +和TRAV1-2-为主的人群过渡到以TRAV1-2 + CD161 ++ CD26 ++的CD8 +人群为主。我们还观察到在分枝杆菌刺激下表达TNF的四聚体+ MR1T细胞在新生儿中非常低，但在生命的第一年增加了约10倍。在所有年龄段中，这些功能性MR1T细胞均为MR1-5-OP-RU四聚体+ TRAV1-2 +，并高度表达CD161和CD26，标志物似乎表明该细胞亚群的表型和功能成熟。这种与年龄相关的成熟还通过四聚体+ TRAV1-2 + MR1T细胞比四聚体+ TRAV1-2- MR1T细胞和非MR1T细胞更快地失去了幼稚T细胞标志物来标记。这些数据表明，新生儿很少出现具有多种表型特征的MR1T细胞。并且这种暴露于环境的速度迅速并优先扩大了MR1T细胞的MR1-5-OP-RU四聚体+ TRAV1-2 +群体，这成为儿童期早期功能性MR1T细胞的主要群体。这些数据表明，新生儿很少出现具有多种表型特征的MR1T细胞。并且这种暴露于环境的速度迅速并优先扩大了MR1T细胞的MR1-5-OP-RU四聚体+ TRAV1-2 +群体，这成为儿童期早期功能性MR1T细胞的主要群体。这些数据表明，新生儿很少出现具有多种表型特征的MR1T细胞。并且这种暴露于环境的速度迅速并优先扩大了MR1T细胞的MR1-5-OP-RU四聚体+ TRAV1-2 +群体，这成为儿童期早期功能性MR1T细胞的主要群体。