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首页> 外文期刊>Nature >T-cell activation by transitory neo-antigens derived from distinct microbial pathways
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T-cell activation by transitory neo-antigens derived from distinct microbial pathways

机译：源自不同微生物途径的瞬时新抗原激活T细胞

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摘要

T cells discriminate between foreign and host molecules by recognizing distinct microbial molecules, predominantly peptides and lipids. Riboflavin precursors found in many bacteria and yeast also selectively activate mucosal-associated invariant T (MAIT) cells, an abundant population of innate-like T cells in humans. However, the genesis of these small organic molecules and their mode of presentation to MAIT cells by the major histocompatibility complex (MHC)-related protein MR1 (ref. 8) are not well understood. Here we show that MAIT-cell activation requires key genes encoding enzymes that form 5-amino-6-D-ribitylaminouracil (5-A-RU), an early intermediate in bacterial riboflavin synthesis. Although 5-A-RU does not bind MR1 or activate MAIT cells directly, it does form potent MAIT-activating antigens via non-enzymatic reactions with small molecules, such as glyoxal and methylglyoxal, which are derived from other metabolic pathways. The MAIT antigens formed by the reactions between 5-A-RU and glyoxal/methylglyoxal were simple adducts, 5-(2-oxoethylideneammo)-6-d-ribitylaminouracil (5-OE-RU) and 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU), respectively, which bound to MR1 as shown by crystal structures of MAIT TCR ternary complexes. Although 5-OP-RU and 5-OE-RU are unstable intermediates, they became trapped by MR1 as reversible cova-lent Schiff base complexes. Mass spectra supported the capture by MR1 of 5-OP-RU and 5-OE-RU from bacterial cultures that activate MAIT cells, but not from non-activating bacteria, indicating that these MAIT antigens are present in a range of microbes. Thus, MR1 is able to capture, stabilize and present chemically unstable pyrimi-dine intermediates, which otherwise convert to lumazines, as potent antigens to MAIT cells. These pyrimidine adducts are microbial signatures for MAIT-cell immunosurveillance.
机译：T细胞通过识别不同的微生物分子（主要是肽和脂质）来区分外来分子和宿主分子。在许多细菌和酵母中发现的核黄素前体还选择性激活粘膜相关不变性T（MAIT）细胞，这是人体内大量的先天性T细胞。但是，这些小有机分子的产生及其通过主要组织相容性复合物（MHC）相关蛋白MR1呈递给MAIT细胞的方式尚不清楚。在这里，我们显示MAIT细胞激活需要关键的基因编码的酶，形成5-氨基-6-D-核糖胺基尿嘧啶（5-A-RU），这是细菌核黄素合成的早期中间体。尽管5-A-RU不会直接结合MR1或激活MAIT细胞，但它会通过与其他代谢途径衍生的小分子（例如乙二醛和甲基乙二醛）的非酶促反应形成有效的MAIT活化抗原。由5-A-RU与乙二醛/甲基乙二醛之间的反应形成的MAIT抗原是简单的加合物，5-（2-氧代乙二酰胺）-6-d-核糖基氨基尿嘧啶（5-OE-RU）和5-（2-氧代丙二胺基）-如MAIT TCR三元复合物的晶体结构所示，分别与MR1结合的6-d-核糖基氨基尿嘧啶（5-OP-RU）。尽管5-OP-RU和5-OE-RU是不稳定的中间体，但它们被MR1捕获为可逆的席夫碱席夫碱复合物。质谱支持MR1从激活MAIT细胞的细菌培养物中捕获5-OP-RU和5-OE-RU，但不捕获未激活细菌，表明这些MAIT抗原存在于一系列微生物中。因此，MR1能够捕获，稳定和呈递化学上不稳定的嘧啶-丁中间体，否则该中间体会转化为柳嗪，作为MAIT细胞的有效抗原。这些嘧啶加合物是MAIT细胞免疫监测的微生物特征。

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  • 来源
    《Nature》 |2014年第7500期|361-365|共5页
  • 作者

    Alexandra J. Corbett; Sidonia B. G. Eckle; Richard W. Birkinshaw; Ligong Liu; Onisha Patel; Jennifer Mahony; Zhenjun Chen; Rangsima Reantragoon; Bronwyn Meehan; Hanwei Cao; Nicholas A. Williamson; Richard A. Strugnell; Douwe Van Sinderen; Jeffrey Y. W. Mak; David P. Fairlie; Lars Kjer-Nielsen; Jamie Rossjohn; James McCluskey;

  • 作者单位

    Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia;

    Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia;

    Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia;

    Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia;

    Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia;

    School of Microbiology, University College Cork, Cork, Ireland;

    Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia;

    Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia;

    Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia;

    Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia;

    The Bio21 Molecular Scienceand Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia;

    Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia;

    School of Microbiology, University College Cork, Cork, Ireland,Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland;

    Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia;

    Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, Queensland 4072, Australia;

    Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia;

    Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia,Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK;

    Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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