Soudais Claire, Samassa Fatoumata, Sarkis Manal, Le Bourhis Lionel, Bessoles Stéphanie, Blanot Didier, Hervé Mireille, Schmidt Frédéric, Mengin-Lecreulx Dominique, Lantz Olivier
INSERM U932, Paris 75005, France;
INSERM U932, Paris 75005, France; Département de Chimie, Institut Curie, Unité Mixte de Recherche 176, Paris 75005, France;
J Immunol. 2015 May 15;194(10):4641-9. doi: 10.4049/jimmunol.1403224. Epub 2015 Apr 13.
Mucosal-associated invariant T (MAIT) cells recognize microbial compounds presented by the MHC-related 1 (MR1) protein. Although riboflavin precursor derivatives from Gram-positive bacteria have been characterized, some level of ligand heterogeneity has been suggested through the analysis of the MAIT cell TCR repertoire in humans and differential reactivity of human MAIT cell clones according to the bacteria. In this study, using Gram-negative bacteria mutated for the riboflavin biosynthetic pathway, we show a strict correlation between the ability to synthesize the 5-amino-ribityl-uracil riboflavin precursor and to activate polyclonal and quasi-monoclonal mouse MAIT cells. To our knowledge, we show for the first time that the semipurified bacterial fraction and the synthetic ligand activate murine MAIT cells in vitro and in vivo. We describe new MR1 ligands that do not activate MAIT cells but compete with bacterial and synthetic compounds activating MAIT cells, providing the capacity to modulate MAIT cell activation. Through competition experiments, we show that the most active synthetic MAIT cell ligand displays the same functional avidity for MR1 as does the microbial compound. Altogether, these results show that most, if not all, MAIT cell ligands found in Escherichia coli are related to the riboflavin biosynthetic pathway and display very limited heterogeneity.
黏膜相关恒定T（MAIT）细胞识别由主要组织相容性复合体相关蛋白1（MR1）呈递的微生物化合物。尽管来自革兰氏阳性菌的核黄素前体衍生物已得到表征，但通过对人类MAIT细胞TCR库的分析以及人类MAIT细胞克隆对不同细菌的差异反应性，提示存在一定程度的配体异质性。在本研究中，我们利用核黄素生物合成途径发生突变的革兰氏阴性菌，发现合成5-氨基核糖基尿嘧啶核黄素前体的能力与激活多克隆和准单克隆小鼠MAIT细胞的能力之间存在严格的相关性。据我们所知，我们首次证明半纯化的细菌组分和合成配体在体外和体内均可激活小鼠MAIT细胞。我们描述了新的MR1配体，它们不激活MAIT细胞，但可与激活MAIT细胞的细菌和合成化合物竞争，从而具备调节MAIT细胞激活的能力。通过竞争实验，我们发现活性最强的合成MAIT细胞配体对MR1的功能亲和力与微生物化合物相同。总之，这些结果表明，在大肠杆菌中发现的大多数（如果不是全部）MAIT细胞配体都与核黄素生物合成途径相关，且异质性非常有限。
