MicroRNA-155 Controls iNKT Cell Development and Lineage Differentiation by Coordinating Multiple Regulating Pathways.
MicroRNA-155 Controls iNKT Cell Development and Lineage Differentiation by Coordinating Multiple Regulating Pathways.
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DOI：
10.3389/fcell.2020.619220
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发表时间：
2020
影响因子：
5.5
通讯作者：
Mi QS
中科院分区：
文献类型：
--
作者：
Wang J;Li K;Zhang X;Li G;Liu T;Wu X;Brown SL;Zhou L;Mi QS
恒定自然杀伤 T (iNKT) 细胞的发育需要一组协调良好的转录因子，但人们对这些因子如何调节和协调仍知之甚少。 MicroRNA-155 (miR-155) 是影响细胞发育和体内平衡的众多细胞过程的关键调节因子。在这里，我们发现miR-155在胸腺选择后的早期iNKT细胞中高表达，然后在iNKT细胞发育过程中其表达逐渐下调。然而，miR-155 种系缺失的小鼠具有正常的 iNKT 细胞发育。为了解决 iNKT 细胞发育是否需要下调 miR-155，我们制作了 CD4Cre.miR-155 敲入 (KI) 小鼠模型，其中 miR-155 在 T 细胞谱系中条件性过表达。 miR-155上调导致iNKT细胞发育中断，iNKT17和iNKT1细胞减少，iNKT2细胞增加，这些缺陷是细胞固有的。此外，miR-155KI 小鼠中的缺陷 iNKT 细胞导致继发性先天样 CD8 T 细胞发育。从机制上讲，miR-155 调节多个靶标和信号通路以微调 iNKT 细胞发育。 MiR-155 调节 Jarid2（组蛋白修饰复合物的关键成分）和 Tab2（NF-κB 的上游激活激酶复合物成分），在 iNKT 发育和促进平衡的 iNKT1/iNKT2 分化中发挥附加作用。此外，miR-155还靶向Rictor，这是控制iNKT17分化的mTORC2的标志性成分。综上所述，我们的结果表明 miR-155 作为一个关键的表观遗传调节因子，协调多个信号通路和转录程序，以精确调节 iNKT 细胞发育和功能谱系，以及次级先天 CD8 T 细胞发育。
The development of invariant natural killer T (iNKT) cells requires a well-attuned set of transcription factors, but how these factors are regulated and coordinated remains poorly understood. MicroRNA-155 (miR-155) is a key regulator of numerous cellular processes that affects cell development and homeostasis. Here, we found that miR-155 was highly expressed in early iNKT cells upon thymic selection, and then its expression is gradually downregulated during iNKT cell development. However, the mice with miR-155 germline deletion had normal iNKT cell development. To address if downregulated miR-155 is required for iNKT cell development, we made a CD4Cre.miR-155 knock-in (KI) mouse model with miR-155 conditional overexpression in the T cell lineage. Upregulated miR-155 led to interruption of iNKT cell development, diminished iNKT17 and iNKT1 cells, augmented iNKT2 cells, and these defects were cell intrinsic. Furthermore, defective iNKT cells in miR-155KI mice resulted in the secondary innate-like CD8 T cell development. Mechanistically, miR-155 modulated multiple targets and signaling pathways to fine tune iNKT cell development. MiR-155 modulated Jarid2, a critical component of a histone modification complex, and Tab2, the upstream activation kinase complex component of NF-κB, which function additively in iNKT development and in promoting balanced iNKT1/iNKT2 differentiation. In addition, miR-155 also targeted Rictor, a signature component of mTORC2 that controls iNKT17 differentiation. Taken together, our results indicate that miR-155 serves as a key epigenetic regulator, coordinating multiple signaling pathways and transcriptional programs to precisely regulate iNKT cell development and functional lineage, as well as secondary innate CD8 T cell development.
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影响因子：
30.5
作者：
通讯作者：
--
影响因子：
8
作者：
Kluiver, J.;van den Berg, A.;Kroesen, B-J
通讯作者：
Kroesen, B-J
DOI：
10.1038/nri3198
发表时间：
2012-04-20
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
32.4
作者：
Escobar, Thelma M.;Kanellopoulou, Chrysi;Kugler, David G.;Kilaru, Gokhul;Nguyen, Cuong K.;Nagarajan, Vijayaraj;Bhairavabhotla, Ravikiran K.;Northrup, Daniel;Zahr, Rami;Burr, Patrick;Liu, Xiuhuai;Zhao, Keji;Sher, Alan;Jankovic, Dragana;Zhu, Jinfang;Muljo, Stefan A.
通讯作者：
Muljo, Stefan A.
影响因子：
7.3
作者：
Burocchi A;Pittoni P;Tili E;Rigoni A;Costinean S;Croce CM;Colombo MP
通讯作者：
Colombo MP