York Biomedical Research Institute, University of York, York, YO10 5DD Yorkshire, United Kingdom.
Department of Biology, University of York, York, YO10 5DD Yorkshire, United Kingdom.
J Immunol. 2020 Jun 1;204(11):2949-2960. doi: 10.4049/jimmunol.1900940. Epub 2020 Apr 22.
Despite extensive mapping of long noncoding RNAs in immune cells, their function in vivo remains poorly understood. In this study, we identify over 100 long noncoding RNAs that are differentially expressed within 24 h of Th1 cell activation. Among those, we show that suppression of is a hallmark of CD4 T cell activation, but its complete deletion results in more potent immune responses to infection. This is because Th1 and Th2 cells express lower levels of the immunosuppressive cytokine IL-10. In vivo, the reduced CD4 T cell IL-10 expression in mice underpins enhanced immunity and pathogen clearance in experimental visceral leishmaniasis () but more severe disease in a model of malaria ( AS). Mechanistically, regulates IL-10 through enhancing expression of Maf, a key transcriptional regulator of Maf expression correlates with in single Ag-specific Th cells from AS-infected mice and is downregulated in Th1 and Th2 cells. The RNA is responsible for these effects, as antisense oligonucleotide-mediated inhibition of also suppresses Maf and IL-10 levels. Our results reveal that through promoting expression of the Maf/IL-10 axis in effector Th cells, is a nonredundant regulator of mammalian immunity.
尽管已经对免疫细胞中的长非编码 RNA 进行了广泛的研究，但它们在体内的功能仍知之甚少。在这项研究中，我们鉴定了超过 100 种在 Th1 细胞激活后 24 小时内差异表达的长非编码 RNA。在这些长非编码 RNA 中，我们发现抑制是 CD4 T 细胞活化的标志，但完全缺失会导致对感染的免疫反应更强烈。这是因为缺失会导致 Th1 和 Th2 细胞表达较低水平的免疫抑制细胞因子 IL-10。在体内，减少的 CD4 T 细胞 IL-10 表达会增强实验性内脏利什曼病（）中的免疫力和病原体清除，但在疟疾（AS）模型中会导致更严重的疾病。从机制上讲，通过增强关键转录调节因子 Maf 的表达来调节 IL-10。Maf 表达与从 AS 感染小鼠中分离的单个 Ag 特异性 Th 细胞中的相关，在 Th1 和 Th2 细胞中下调。的 RNA 负责这些效应，因为反义寡核苷酸介导的抑制也会抑制 Maf 和 IL-10 水平。我们的结果表明，通过在效应 Th 细胞中促进 Maf/IL-10 轴的表达，是哺乳动物免疫的非冗余调节剂。
