MicroRNA-126 regulates the induction and function of CD4(+) Foxp3(+) regulatory T cells through PI3K/AKT pathway.
MicroRNA-126 regulates the induction and function of CD4(+) Foxp3(+) regulatory T cells through PI3K/AKT pathway.
复制标题
MicroRNA-126通过PI3K/AKT途径调节CD4 Foxp3调节性T细胞的诱导和功能
DOI：
10.1111/jcmm.12003
复制
发表时间：
2013-02
影响因子：
5.3
通讯作者：
Xu L
中科院分区：
文献类型：
--
作者：
Qin A;Wen Z;Zhou Y;Li Y;Li Y;Luo J;Ren T;Xu L
近年来的研究表明，PI 3 K/Akt通路的有限激活对于CD 4 + Foxp 3+调节性T细胞（Treg）的诱导和功能维持至关重要。然而，其潜在的机制在很大程度上仍不清楚。在这项研究中，我们报道了miR-126在小鼠和人Tcells中表达。进一步的研究表明，使用miR-126反义寡核苷酸（阿索）沉默miR-126可以显著降低体外TcB的诱导。此外，miR-126沉默可明显降低Foxp 3在TGFAP上的表达，并伴随CTLA-4、GITR、IL-10、TGF-β表达的降低，削弱其抑制功能。机制证据表明，沉默miR-126增强了其靶点p85β的表达，随后改变了PI 3 K/Akt通路的激活，这最终导致Tcl 3的诱导和抑制功能降低。最后，我们进一步揭示了miR-126沉默可以在体内削弱T细胞的抑制功能，并在使用小鼠乳腺癌模型的过继细胞转移试验中赋予CD 8 +T细胞有效的抗肿瘤作用。因此，我们的研究表明，miR-126可以作为微调器调节PI 3 K-Akt通路转导，诱导和持续抑制TclO的功能，并提供了一个新的见解，通过靶向特定的miRNA调节TclO来促进T细胞免疫的治疗策略的发展。
Recent evidence showed that limited activation of PI3K/Akt pathway was critical for induction and function sustainment of CD4+Foxp3+ regulatory T cells (Tregs). However, the underlying mechanism remains largely unknown. In this study, we reported that miR‐126 was expressed in mouse and human Tregs. Further study showed that silencing of miR‐126 using miR‐126 antisense oligonucleotides (ASO) could significantly reduce the induction of Tregs in vitro. Furthermore, miR‐126 silencing could obviously reduce the expression of Foxp3 on Tregs, which was accompanied by decreased expression of CTLA‐4 and GITR, as well as IL‐10 and TGF‐β, and impair its suppressive function. Mechanistic evidence showed that silencing of miR‐126 enhanced the expression of its target p85β and subsequently altered the activation of PI3K/Akt pathway, which was ultimately responsible for reduced induction and suppressive function of Tregs. Finally, we further revealed that miR‐126 silencing could impair the suppressive function of Tregs in vivo and endow effectively antitumour effect of CD8+T cells in adoptive cell transfer assay using a murine breast cancer model. Therefore, our study showed that miR‐126 could act as fine‐tuner in regulation of PI3K‐Akt pathway transduction in the induction and sustained suppressive function of Tregs and provided a novel insight into the development of therapeutic strategies for promoting T‐cell immunity by regulating Tregs through targeting specific miRNAs.
登录
查看更多内容
影响因子：
3.7
作者：
Guo, Chunguang;Sah, Jerome F.;Beard, Lydia;Willson, James K. V.;Markowitz, Sanford D.;Guda, Kishore
通讯作者：
Guda, Kishore
影响因子：
20.3
作者：
Jiang, Shan;Li, Chaoran;Li, Qi-Jing
通讯作者：
Li, Qi-Jing
影响因子：
32.4
作者：
Lu, Li-Fan;Thai, To-Ha;Calado, Dinis Pedro;Chaudhry, Ashutosh;Kubo, Masato;Tanaka, Kentaro;Loeb, Gabriel B.;Lee, Hana;Yoshimura, Akihiko;Rajewsky, Klaus;Rudensky, Alexander Y.
通讯作者：
Rudensky, Alexander Y.
影响因子：
29.7
作者：
Josefowicz SZ;Lu LF;Rudensky AY
通讯作者：
Rudensky AY
DOI：
10.1073/pnas.0905063106
发表时间：
2009-11-03
影响因子：
11.1
作者：
Mattes, Joerg;Collison, Adam;Foster, Paul S.
通讯作者：
Foster, Paul S.