T-cell activation by transitory neo-antigens derived from distinct microbial pathways
T-cell activation by transitory neo-antigens derived from distinct microbial pathways
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DOI：
10.1038/nature13160
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发表时间：
2014-05-15
期刊：
影响因子：
64.8
通讯作者：
McCluskey, James
中科院分区：
文献类型：
--
作者：
Corbett, Alexandra J.;Eckle, Sidonia B. G.;McCluskey, James
T细胞通过识别不同的微生物分子来区分外来分子和宿主分子，主要是肽和脂质（1-4）。在许多细菌和酵母中发现的核黄素前体也选择性地激活粘膜相关不变T （MAIT）细胞（5,6），这是人类中大量的先天样T细胞（7-9）。然而，这些小有机分子的起源及其通过主要组织相容性复合体（MHC）相关蛋白MR1向MAIT细胞呈递的模式（参考文献8）尚不清楚。在这里，我们发现mait细胞的激活需要编码5-氨基-6- d -核糖氨基尿嘧啶（5-A-RU）酶的关键基因，5-A-RU是细菌核黄素合成的早期中间体。虽然5-A-RU不结合MR1或直接激活MAIT细胞，但它确实通过与小分子（如乙二醛和甲基乙二醛）的非酶反应形成有效的MAIT激活抗原，这些小分子来源于其他代谢途径。5- a - ru与乙二醛/甲基乙二醛反应形成的MAIT抗原分别为简单加合物5-（2-氧乙基氨基）-6- d -ribitylaminouracil （5- oe - ru）和5-（2-氧丙基氨基）-6- d -ribitylaminouracil (5- op - ru)，从MAIT TCR三元配合物的晶体结构可以看出它们与MR1结合。虽然5-OP-RU和5- e - ru是不稳定的中间体，但它们被MR1捕获为可逆的共价希夫碱配合物。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，而不是从非激活细菌中捕获，表明这些MAIT抗原存在于一系列微生物中。因此，MR1能够捕获、稳定并呈现化学上不稳定的嘧啶中间体，否则这些中间体会转化为lumazines，作为MAIT细胞的有效抗原。这些嘧啶加合物是mait细胞免疫监视的微生物特征。
T cells discriminate between foreign and host molecules by recognizing distinct microbial molecules, predominantly peptides and lipids(1-4). Riboflavin precursors found in many bacteria and yeast also selectively activate mucosal-associated invariant T (MAIT) cells(5,6), an abundant population of innate-like T cells in humans(7-9). 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-oxoethylideneamino)-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 covalent 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 pyrimidine intermediates, which otherwise convert to lumazines, as potent antigens to MAIT cells. These pyrimidine adducts are microbial signatures for MAIT-cell immunosurveillance.