Lin28b Regulates Fetal Regulatory T Cell Differentiation through Modulation of TGF-β Signaling.
Lin28b Regulates Fetal Regulatory T Cell Differentiation through Modulation of TGF-β Signaling.
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DOI：
10.4049/jimmunol.1601070
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发表时间：
2016-12-01
期刊：
影响因子：
--
通讯作者：
McCune JM
中科院分区：
文献类型：
--
作者：
Bronevetsky Y;Burt TD;McCune JM
胎儿和母亲之间的免疫耐受代表了一个活跃的过程，通过该过程，发育中的胎儿不得对驻留在胎儿组织中的嵌合母体细胞上的非遗传性抗原产生免疫反应。这部分是由 CD4+FoxP3+CD25+ 调节性 T 细胞 (Treg) 的抑制影响介导的。胎儿次级淋巴器官的 Tregs 频率增加，与成人 T 细胞相比，胎儿幼稚 CD4+ T 细胞在受到刺激时表现出分化为 Tregs 的强烈倾向。这种效应是由 T 细胞受体 (TCR) 和 TGF-β 通路介导的，胎儿 T 细胞响应抗 CD3 和 TGF-β 刺激，表现出显着增加的 Treg 分化。幼稚胎儿 T 细胞还表现出通过 TGF-β 途径的信号传导增加，这些细胞表现出信号传导介质 TGF-βRI、TGF-βRIII 和 SMAD2 表达增加，以及 SMAD2/SMAD3 磷酸化水平升高。胎儿 Treg 分化的增加是由 RNA 结合蛋白 Lin28b 介导的，与成人细胞相比，该蛋白在胎儿 T 细胞中过度表达。当幼稚胎儿 T 细胞中 Lin28b 表达减少时，它们表现出 Treg 分化减少，这与 TGF-β 信号传导减少以及 TGF-βRI、TGF-βRIII 和 SMAD2 表达降低相关。 Lin28b 调节 let-7 microRNA (miRNA) 的成熟，这些 TGF-β 信号传导介质是 let-7 的靶标。我们假设胎儿 T 细胞中 Lin28b 表达的缺失会导致成熟 let-7 的增加，从而导致 TGF-βRI、TGF-βRIII 和 SMAD2 蛋白的表达减少。 TGF-β 信号传导的减少会导致 Treg 数量减少。
Immune tolerance between the fetus and mother represents an active process by which the developing fetus must not mount immune responses to non-inherited antigens on chimeric maternal cells that reside in fetal tissue. This is, in part, mediated by the suppressive influence of CD4+FoxP3+CD25+ regulatory T cells (Tregs). Fetal secondary lymphoid organs have an increased frequency of Tregs and, as compared to adult T cells, fetal naïve CD4+ T cells exhibit a strong predisposition to differentiate into Tregs when stimulated. This effect is mediated by the T cell receptor (TCR) and TGF-β pathways, and fetal T cells show significantly increased Treg differentiation in response to anti-CD3 and TGF-β stimulation. Naïve fetal T cells also exhibit increased signaling through the TGF-β pathway, with these cells demonstrating increased expression of the signaling mediators TGF-βRI, TGF-βRIII, and SMAD2, and higher levels of SMAD2/SMAD3 phosphorylation. Increased fetal Treg differentiation is mediated by the RNA-binding protein Lin28b, which is overexpressed in fetal T cells as compared to adult cells. When Lin28b expression is decreased in naïve fetal T cells, they exhibit decreased Treg differentiation that is associated with decreased TGF-β signaling and lowered expression of TGF-βRI, TGF-βRIII, and SMAD2. Lin28b regulates the maturation of let-7 microRNAs (miRNAs) and these TGF-β signaling mediators are let-7 targets. We hypothesize that loss of Lin28b expression in fetal T cells leads to increased mature let-7, which causes decreased expression of TGF-βRI, TGF-βRIII, and SMAD2 proteins. A reduction in TGF-β signaling leads to reduced Treg numbers.
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