Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA.
Department of Computational Biology, Oregon Health and Science University, Portland, OR, USA.
Sci Rep. 2020 Sep 22;10(1):15429. doi: 10.1038/s41598-020-72394-9.
Mucosal Associated Invariant T (MAIT) cells can sense intracellular infection by a broad array of pathogens. These cells are activated upon encountering microbial antigen(s) displayed by MR1 on the surface of an infected cell. Human MR1 undergoes alternative splicing. The full-length isoform, MR1A, can activate MAIT cells, while the function of the isoforms, MR1B and MR1C, are incompletely understood. In this report, we sought to characterize the expression and function of these splice variants. Using a transcriptomic analysis in conjunction with qPCR, we find that that MR1A and MR1B transcripts are widely expressed. However only MR1A can present mycobacterial antigen to MAIT cells. Coexpression of MR1B with MR1A decreases MAIT cell activation following bacterial infection. Additionally, expression of MR1B prior to MR1A lowers total MR1A abundance, suggesting competition between MR1A and MR1B for either ligands or chaperones required for folding and/or trafficking. Finally, we evaluated CD4/CD8 double positive thymocytes expressing surface MR1. Here, we find that relative expression of MR1A/MR1B transcript is associated with the prevalence of MR1 + CD4/CD8 cells in the thymus. Our results suggest alternative splicing of MR1 represents a means of regulating MAIT activation in response to microbial ligand(s).
黏膜相关不变 T（MAIT）细胞可以感知多种病原体的细胞内感染。这些细胞在遇到感染细胞表面 MR1 展示的微生物抗原时被激活。人类 MR1 经历可变剪接。全长异构体 MR1A 可以激活 MAIT 细胞，而异构体 MR1B 和 MR1C 的功能尚不完全清楚。在本报告中，我们试图表征这些剪接变体的表达和功能。使用转录组分析结合 qPCR，我们发现 MR1A 和 MR1B 转录本广泛表达。然而，只有 MR1A 才能将分枝杆菌抗原呈递给 MAIT 细胞。MR1B 与 MR1A 共表达会降低细菌感染后 MAIT 细胞的激活。此外，MR1A 之前表达 MR1B 会降低总 MR1A 丰度，表明 MR1A 和 MR1B 之间存在竞争，争夺折叠和/或运输所需的配体或伴侣分子。最后，我们评估了表达表面 MR1 的 CD4/CD8 双阳性胸腺细胞。在这里，我们发现 MR1A/MR1B 转录本的相对表达与胸腺中 MR1+CD4/CD8 细胞的流行程度相关。我们的结果表明，MR1 的可变剪接代表了一种调节 MAIT 激活以响应微生物配体的方式。
