Molecular dissection of the miR-17-92 cluster's critical dual roles in promoting Th1 responses and preventing inducible Treg differentiation
Molecular dissection of the miR-17-92 cluster's critical dual roles in promoting Th1 responses and preventing inducible Treg differentiation
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DOI：
10.1182/blood-2011-05-355644
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发表时间：
2011-11-17
期刊：
影响因子：
20.3
通讯作者：
Li, Qi-Jing
中科院分区：
文献类型：
--
作者：
Jiang, Shan;Li, Chaoran;Li, Qi-Jing
Mir - 17 - 92在单个多顺反子转录本内编码6种微小RNA（miRNA），其正确表达对早期B细胞发育和淋巴细胞内稳态至关重要。然而，在T细胞抗原应答过程中，内源性miR - 17 - 92的生理功能以及单个miRNA的作用仍不明确。在本研究中，我们对miR - 17 - 92簇进行了功能解析，发现miR - 17和miR - 19b是通过多种协同的生物学过程控制Th1应答的关键因子。这些过程包括：促进增殖、保护细胞免受活化诱导的细胞死亡、支持干扰素 - γ的产生以及抑制诱导性调节性T细胞分化。从机制上讲，我们确定Pten（磷酸酶和张力蛋白同源物）是miR - 19b具有重要功能的靶标，而miR - 17的功能是由转化生长因子β受体II（TGFβRII）和新靶标CREB1介导的。由于其对Th1细胞 - 诱导性调节性T细胞平衡的有力控制，CD4 T细胞中miR - 17 - 92的缺失导致肿瘤逃逸。我们的研究结果表明，miR - 19b和miR - 17可被用于提高基于T细胞的肿瘤治疗的疗效。（《血液》2011年；118(20):5487 - 5497）
Mir-17-92 encodes 6 miRNAs inside a single polycistronic transcript, the proper expression of which is critical for early B-cell development and lymphocyte homeostasis. However, during the T-cell antigen response, the physiologic function of endogenous miR-17-92 and the roles of the individual miRNAs remain elusive. In the present study, we functionally dissected the miR-17-92 cluster and revealed that miR-17 and miR-19b are the key players controlling Th1 responses through multiple coordinated biologic processes. These include: promoting proliferation, protecting cells from activation-induced cell death, supporting IFN-gamma production, and suppressing inducible regulatory T-cell differentiation. Mechanistically, we identified Pten (iphosphatase and tensin homolog) as the functionally important target of miR-19b, whereas the function of miR-17 is mediated by TGF beta RII and the novel target CREB1. Because of its vigorous control over the Th1 cell-inducible regulatory T cell balance, the loss of miR-17-92 in CD4 T cells results in tumor evasion. Our results suggest that miR-19b and miR-17 could be harnessed to enhance the efficacy of T cell-based tumor therapy. (Blood. 2011;118(20):5487-5497)