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TLR signaling in human antigen‐presenting cells regulates MR1‐dependent activation of MAIT cells

机译:人抗原呈递细胞中的TLR信号传导调节MAIT细胞的MR1依赖性激活

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摘要

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.
机译:粘膜相关不变T(MAIT)细胞是丰富的先天样T淋巴细胞,在肝脏和粘膜组织中富集。它们受到MR1的限制,MR1呈现源自核黄素合成代谢前体的抗原,核黄素合成是许多微生物物种(包括共生微生物)中存在的途径。因此,必须严格调节MR1介导的MAIT细胞激活,以防止不适当的激活和免疫病理学。我们使用MR1介导的人类MAIT细胞活化的体外模型,研究了其调控机制。有效的MR1介导的MAIT细胞活化需要抗原呈递细胞(APC)吸收完整细菌进入酸化的溶酶体区室,而可溶性配体刺激效率低下。与此相一致,在人类单核细胞(THP1)和B细胞系的表面几乎未见MR1。用TLR配体激活会增加THP1表面的MR1数量,但不会增加B细胞系的数量,表明在不同细胞类型中存在差异调节。 APC激活和NF-κB信号传导对于MR1介导的MAIT细胞激活至关重要。然而,在原代细胞中,延长的TLR信号传导导致MR1介导的MAIT细胞激活的下调。总体而言,MR1介导的MAIT细胞激活是一个严格调控的过程,取决于APC对先天信号的整合。

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