Human mucosal-associated invariant T (MAIT) cell receptors (TCRs) recognize bacterial riboflavin pathway metabolites through the MHC class 1-related molecule MR1. However, it is unclear whether MAIT cells discriminate between many species of the human microbiota. To address this, we developed an in vitro functional assay through human T cells engineered for MAIT-TCRs (eMAIT-TCRs) stimulated by MR1-expressing antigen-presenting cells (APCs). We then screened 47 microbiota-associated bacterial species from different phyla for their eMAIT-TCR stimulatory capacities. Only bacterial species that encoded the riboflavin pathway were stimulatory for MAIT-TCRs. Most species that were high stimulators belonged to Bacteroidetes and Proteobacteria phyla, whereas low/non-stimulator species were primarily Actinobacteria or Firmicutes. Activation of MAIT cells by high- vs low-stimulating bacteria also correlated with the level of riboflavin they secreted or after bacterial infection of macrophages. Remarkably, we found that human T-cell subsets can also present riboflavin metabolites to MAIT cells in a MR1-restricted fashion. This T-T cell-mediated signaling also induced IFNγ, TNF and granzyme B from MAIT cells, albeit at lower level than professional APC. These findings suggest that MAIT cells can discriminate and categorize complex human microbiota through computation of TCR signals depending on antigen load and presenting cells, and fine-tune their functional responses.

中文翻译：

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通过共生细菌物种和 MR1 依赖性 T 细胞呈递调节人 MAIT 细胞活化。

人类粘膜相关不变 T (MAIT) 细胞受体 (TCR) 通过 MHC 1 类相关分子 MR1 识别细菌核黄素途径代谢物。然而，尚不清楚 MAIT 细胞是否可以区分人类微生物群的许多物种。为了解决这个问题，我们通过为 MAIT-TCR (eMAIT-TCR) 设计的人类 T 细胞开发了一种体外功能测定，该 T 细胞由表达 MR1 的抗原呈递细胞 (APC) 刺激。然后，我们筛选了来自不同门的 47 种微生物群相关细菌物种的 eMAIT-TCR 刺激能力。只有编码核黄素途径的细菌物种才能刺激 MAIT-TCR。大多数高刺激物种属于拟杆菌门和变形杆菌门，而低/非刺激物种主要是放线菌门或厚壁菌门。高刺激和低刺激细菌对 MAIT 细胞的激活也与它们分泌的核黄素水平或细菌感染巨噬细胞后的水平相关。值得注意的是，我们发现人类 T 细胞亚群也可以以 MR1 限制的方式将核黄素代谢物呈递给 MAIT 细胞。这种 TT 细胞介导的信号转导也诱导来自 MAIT 细胞的 IFNγ、TNF 和颗粒酶 B，尽管水平低于专职 APC。这些发现表明，MAIT 细胞可以根据抗原载量和呈递细胞通过计算 TCR 信号来区分和分类复杂的人类微生物群，并微调它们的功能反应。我们发现人类 T 细胞亚群也可以以 MR1 限制的方式将核黄素代谢物呈递给 MAIT 细胞。这种 TT 细胞介导的信号转导也诱导来自 MAIT 细胞的 IFNγ、TNF 和颗粒酶 B，尽管水平低于专职 APC。这些发现表明，MAIT 细胞可以根据抗原载量和呈递细胞通过计算 TCR 信号来区分和分类复杂的人类微生物群，并微调它们的功能反应。我们发现人类 T 细胞亚群也可以以 MR1 限制的方式将核黄素代谢物呈递给 MAIT 细胞。这种 TT 细胞介导的信号转导也诱导来自 MAIT 细胞的 IFNγ、TNF 和颗粒酶 B，尽管水平低于专职 APC。这些发现表明，MAIT 细胞可以根据抗原载量和呈递细胞通过计算 TCR 信号来区分和分类复杂的人类微生物群，并微调它们的功能反应。