Moffett Howell F, Cartwright Adam N R, Kim Hye-Jung, Godec Jernej, Pyrdol Jason, Äijö Tarmo, Martinez Gustavo J, Rao Anjana, Lu Jun, Golub Todd R, Cantor Harvey, Sharpe Arlene H, Novina Carl D, Wucherpfennig Kai W
Department of Cancer Immunology &Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
Nat Immunol. 2017 Jul;18(7):791-799. doi: 10.1038/ni.3755. Epub 2017 May 22.
During infection, antigen-specific T cells undergo tightly regulated developmental transitions controlled by transcriptional and post-transcriptional regulation of gene expression. We found that the microRNA miR-31 was strongly induced by activation of the T cell antigen receptor (TCR) in a pathway involving calcium and activation of the transcription factor NFAT. During chronic infection with lymphocytic choriomeningitis virus (LCMV) clone 13, miR-31-deficent mice recovered from clinical disease, while wild-type mice continued to show signs of disease. This disease phenotype was explained by the presence of larger numbers of cytokine-secreting LCMV-specific CD8 T cells in miR-31-deficent mice than in wild-type mice. Mechanistically, miR-31 increased the sensitivity of T cells to type I interferons, which interfered with effector T cell function and increased the expression of several proteins related to T cell dysfunction during chronic infection. These studies identify miR-31 as an important regulator of T cell exhaustion in chronic infection.
在感染过程中，抗原特异性T细胞经历由基因表达的转录和转录后调控所控制的严格调控的发育转变。我们发现，微小RNA miR-31在涉及钙和转录因子NFAT激活的途径中，通过T细胞抗原受体（TCR）的激活而被强烈诱导。在慢性淋巴细胞性脉络丛脑膜炎病毒（LCMV）克隆13感染期间，miR-31缺陷小鼠从临床疾病中恢复，而野生型小鼠则继续表现出疾病迹象。这种疾病表型可以通过miR-31缺陷小鼠中分泌细胞因子的LCMV特异性CD8 T细胞数量比野生型小鼠中更多来解释。从机制上讲，miR-31增加了T细胞对I型干扰素的敏感性，这干扰了效应T细胞功能，并增加了慢性感染期间与T细胞功能障碍相关的几种蛋白质的表达。这些研究确定miR-31是慢性感染中T细胞耗竭的重要调节因子。
