TLR signaling in human antigen-presenting cells regulates MR1-dependent activation of MAIT cells.
TLR signaling in human antigen-presenting cells regulates MR1-dependent activation of MAIT cells.
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DOI：
10.1002/eji.201545969
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发表时间：
2016-07
影响因子：
5.4
通讯作者：
Klenerman P
中科院分区：
文献类型：
--
作者：
Ussher JE;van Wilgenburg B;Hannaway RF;Ruustal K;Phalora P;Kurioka A;Hansen TH;Willberg CB;Phillips RE;Klenerman P
粘膜相关不变T细胞(MAIT)是一类丰富的天然类T淋巴细胞，主要分布于肝脏和粘膜组织中。它们受到MR1的限制，MR1提出的抗原来自核黄素合成的代谢前体，核黄素合成是许多微生物物种中存在的一条途径，包括共生体。因此，必须严格调控MR1介导的MAIT细胞激活，以防止不适当的激活和免疫病理。利用MR1介导的原代人MAIT细胞激活的体外模型，我们研究了它的调节机制。为了有效地激活MR1介导的MAIT细胞，需要抗原提呈细胞(APC)将完整的细菌摄取到酸化的内溶酶体隔室，而可溶性配体的刺激是无效的。与此相一致的是，人单核细胞(THP1)和B细胞系表面仅有少量的MR1。TLR配体的激活增加了THP1表面的MR1的数量，但不增加B细胞系的MR1的数量，这表明在不同类型的细胞中存在差异调节。APC活化和NF-κB信号转导是MR1介导的MAIT细胞活化的关键。然而，在原代细胞中，延长的TLR信号导致MR1介导的MAIT细胞激活下调。总体而言，MR1介导的MAIT-细胞激活是一个严格调控的过程，依赖于APC对固有信号的整合。
Mucosal‐associated invariant T (MAIT) cells are an abundant innate‐like T lymphocyte population that are enriched in liver and mucosal tissues. They are restricted by MR1, which presents antigens derived from a metabolic precursor of riboflavin synthesis, a pathway present in many microbial species, including commensals. Therefore, MR1‐mediated MAIT cell activation must be tightly regulated to prevent inappropriate activation and immunopathology. Using an in vitro model of MR1‐mediated activation of primary human MAIT cells, we investigated the mechanisms by which it is regulated. Uptake of intact bacteria by antigen presenting cells (APCs) into acidified endolysosomal compartments was required for efficient MR1‐mediated MAIT cell activation, while stimulation with soluble ligand was inefficient. Consistent with this, little MR1 was seen at the surface of human monocytic (THP1) and B‐cell lines. Activation with a TLR ligand increased the amount of MR1 at the surface of THP1 but not B‐cell lines, suggesting differential regulation in different cell types. APC activation and NF‐κB signaling were critical for MR1‐mediated MAIT cell activation. In primary cells, however, prolonged TLR signaling led to downregulation of MR1‐mediated MAIT cell activation. Overall, MR1‐mediated MAIT cell activation is a tightly regulated process, dependent on integration of innate signals by APCs.