Activation of miR-21-Regulated Pathways in Immune Aging Selects against Signatures Characteristic of Memory T Cells
Activation of miR-21-Regulated Pathways in Immune Aging Selects against Signatures Characteristic of Memory T Cells
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DOI：
10.1016/j.celrep.2018.10.074
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发表时间：
2018-11-20
期刊：
影响因子：
8.8
通讯作者：
Goronzy, Jorg J.
中科院分区：
文献类型：
--
作者：
Kim, Chulwoo;Hu, Bin;Goronzy, Jorg J.
保护性疫苗反应的诱导是由抗原特异性抗体和长寿命记忆 T 细胞的成功生成所控制的，但随着年龄的增长，这种反应越来越受到损害。 microRNA 动态网络对 T 细胞蛋白质组的调节对于 T 细胞反应至关重要。在这里，我们发现激活诱导的 miR-21 上调使分化 T 细胞的转录组偏离记忆 T 细胞，而偏向炎症效应 T 细胞。这种转录组偏差也是 miR-21 表达增加的老年人 T 细胞反应的特征，并且可以通过拮抗 miR-21 来逆转。 miR-21 针对多个信号通路中的负反馈回路。 miR-21（高）T 细胞中这些信号通路的协同、持续活性不利于诱导参与记忆细胞分化的转录因子网络。我们的数据表明，抑制老年人中 miR-21 的上调或活性可能会提高他们发起有效疫苗反应的能力。
Induction of protective vaccine responses, governed by the successful generation of antigen-specific antibodies and long-lived memory T cells, is increasingly impaired with age. Regulation of the T cell proteome by a dynamic network of microRNAs is crucial to T cell responses. Here, we show that activation-induced upregulation of miR-21 biases the transcriptome of differentiating T cells away from memory T cells and toward inflammatory effector T cells. Such a transcriptome bias is also characteristic of T cell responses in older individuals who have increased miR-21 expression and is reversed by antagonizing miR-21. miR-21 targets negative feedback circuits in several signaling pathways. The concerted, sustained activity of these signaling pathways in miR-21(high) T cells disfavors the induction of transcription factor networks involved in memory cell differentiation. Our data suggest that curbing miR-21 upregulation or activity in older individuals may improve their ability to mount effective vaccine responses.