miR-466a Targeting of TGF-β2 Contributes to FoxP3(+) Regulatory T Cell Differentiation in a Murine Model of Allogeneic Transplantation.
miR-466a Targeting of TGF-β2 Contributes to FoxP3(+) Regulatory T Cell Differentiation in a Murine Model of Allogeneic Transplantation.
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DOI：
10.3389/fimmu.2018.00688
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发表时间：
2018
影响因子：
7.3
通讯作者：
Nagarkatti PS
中科院分区：
文献类型：
--
作者：
Becker W;Nagarkatti M;Nagarkatti PS
通过调节性T细胞(Treg)控制效应器T细胞功能来诱导免疫耐受的前景对于开发未来治疗同种异体排斥反应和炎症性自身免疫性疾病的治疗策略至关重要。在目前的研究中，我们使用小鼠同种异体移植排斥反应作为模型来识别microRNA(MiRNA)对Treg从幼稚的CD4细胞分化的调控。我们对接受同基因或同种异体移植的小鼠引流淋巴结(DLN)中的CD4+T细胞进行miRNA表达阵列，以确定阻碍Tregs扩张的分子机制。我们发现异基因移植后CD_4+T细胞中的miRNA297-669(C2MC)簇增加，27个上调的miRNAs中有10个都来自这个簇，其中一个成员MMU-miR-466a-3p(miR-466a-3p)以转化生长因子β2(TGFR-β2)为靶标。将miR-466a-3p导入CD4+T细胞后，可诱导的FoxP3+Treg生成减少，同时通过锁定核酸抑制miR-466a-3p的表达，导致Tregs增加，效应T细胞减少。此外，在同种异体皮肤移植模型中，体内抑制miR-466a-3p可通过增加转化生长因子-β2来减弱T细胞对移植物的反应。转化生长因子-β2在诱导Tregs和过继转移方面与转化生长因子-β1一样有效，减轻宿主效应者对移植物的T细胞反应。总之，本研究首次证明了miRNA-466a-3p和转化生长因子-β2在调节Treg分化中的新作用，从而为控制炎性疾病提供了新的途径。
The promise of inducing immunological tolerance through regulatory T cell (Treg) control of effector T cell function is crucial for developing future therapeutic strategies to treat allograft rejection as well as inflammatory autoimmune diseases. In the current study, we used murine allograft rejection as a model to identify microRNA (miRNA) regulation of Treg differentiation from naïve CD4 cells. We performed miRNA expression array in CD4+ T cells in the draining lymph node (dLN) of mice which received syngeneic or allogeneic grafts to determine the molecular mechanisms that hinder the expansion of Tregs. We identified an increase in miRNA cluster 297-669 (C2MC) after allogeneic transplantation, in CD4+ T cells, such that 10 of the 27 upregulated miRNAs were all from this cluster, with one of its members, mmu-miR-466a-3p (miR-466a-3p), targeting transforming growth factor beta 2 (TGF-β2), as identified through reporter luciferase assay. Transfection of miR-466a-3p in CD4+ T cells led to a decreased inducible FoxP3+ Treg generation while inhibiting miR-466a-3p expression through locked nucleic acid resulting in increased Tregs and a reduction in effector T cells. Furthermore, in vivo inhibition of miR-466a-3p in an allogeneic skin-graft model attenuated T cell response against the graft through an increase in TGF-β2. TGF-β2 was as effective as TGF-β1 at both inducing Tregs and through adoptive transfer, mitigating host effector T cell response against the allograft. Together, the current study demonstrates for the first time a new role for miRNA-466a-3p and TGF-β2 in the regulation of Treg differentiation and thus offers novel avenues to control inflammatory disorders.
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DOI：
10.4049/jimmunol.1002937
发表时间：
2011-04-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Mellor AL;Munn DH
通讯作者：
Munn DH
DOI：
10.1038/nri3494
发表时间：
2013-09
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
15.9
作者：
Murugaiyan, Gopal;da Cunha, Andre Pires;Weiner, Howard L.
通讯作者：
Weiner, Howard L.
影响因子：
82.9
作者：
Gagliani, Nicola;Magnani, Chiara F.;Roncarolo, Maria-Grazia
通讯作者：
Roncarolo, Maria-Grazia
胸腺FOXP3（+）调节性T细胞的开发：TGF-β事项。
影响因子：
5.4
作者：
Chen, WanJun;Konkel, Joanne E.
通讯作者：
Konkel, Joanne E.