MicroRNA miR-155 is required for expansion of regulatory T cells to mediate robust pregnancy tolerance in mice.,Mucosal Immunology

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MicroRNA miR-155 is required for expansion of regulatory T cells to mediate robust pregnancy tolerance in mice.
Mucosal Immunology ( IF 7.9 ) Pub Date : 2020-01-27 , DOI: 10.1038/s41385-020-0255-0
John E Schjenken ₁ , Lachlan M Moldenhauer ₁ , Bihong Zhang ₁ , Alison S Care ₁ , Holly M Groome ₁ , Hon-Yeung Chan ₁ , Christopher M Hope ₁ , Simon C Barry ₁ , Sarah A Robertson ₁

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The immune-regulatory microRNA miR-155 is reduced in recurrent miscarriage, suggesting that miR-155 contributes to immune tolerance in pregnancy. Here we show miR-155 is induced in the uterine mucosa and draining lymph nodes (dLN) during the female immune response to male seminal fluid alloantigens. Mice with null mutation in miR-155 (miR-155-/-) exhibited a reduced CD4+ T cell response after mating, with a disproportionate loss of CD25+FOXP3+ Treg cells. miR-155 deficiency impaired expansion of both peripheral and thymic Treg cells, distinguished by neuropilin-1 (NRP1), and fewer Treg cells expressed Ki67 proliferation marker and suppressive function marker CTLA4. Altered Treg phenotype distribution in miR-155-/- mice was confirmed by t-distributed neighbor embedding (tSNE) analysis. Fewer dendritic cells (DCs) and macrophages trafficked to the dLN of miR-155-/- mice, associated with lower CCR7 on DCs, and reduced uterine Ccl19 expression, implicating compromised antigen presentation in the stunted Treg cell response. miR-155-/- mice exhibited elevated susceptibility to inflammation-induced fetal loss and fetal growth restriction compared with miR-155+/+ controls, but outcomes were restored by transfer of wild-type Tregs. Thus miR-155 is a key regulator of immune adaptation to pregnancy and is necessary for sufficient Tregs to achieve robust pregnancy tolerance and protect against fetal loss.

中文翻译：

MicroRNA miR-155 是扩增调节性 T 细胞以介导小鼠强大的妊娠耐受性所必需的。

免疫调节 microRNA miR-155 在反复流产中减少，表明 miR-155 有助于妊娠期的免疫耐受。在这里，我们显示在女性对男性精液同种异体抗原的免疫反应期间，miR-155 在子宫粘膜和引流淋巴结 (dLN) 中被诱导。miR-155 无效突变的小鼠 (miR-155-/-) 在交配后表现出 CD4+ T 细胞反应降低，CD25+FOXP3+ Treg 细胞不成比例地丢失。miR-155 缺陷损害了外周和胸腺 Treg 细胞的扩张，以 neuropilin-1 (NRP1) 为特征，更少的 Treg 细胞表达 Ki67 增殖标志物和抑制功能标志物 CTLA4。通过 t 分布邻域嵌入 (tSNE) 分析证实了 miR-155-/- 小鼠中改变的 Treg 表型分布。更少的树突状细胞 (DC) 和巨噬细胞被转运到 miR-155-/- 小鼠的 dLN，与 DC 上较低的 CCR7 和子宫 Ccl19 表达减少相关，这表明 Treg 细胞反应受阻的抗原呈递受损。与 miR-155+/+ 对照相比，miR-155-/- 小鼠对炎症诱导的胎儿丢失和胎儿生长受限表现出更高的易感性，但通过转移野生型 Treg 恢复了结果。因此，miR-155 是妊娠免疫适应的关键调节因子，是足够的 Treg 实现强妊娠耐受和防止胎儿丢失所必需的。与 miR-155+/+ 对照相比，miR-155-/- 小鼠对炎症诱导的胎儿丢失和胎儿生长受限表现出更高的易感性，但通过转移野生型 Treg 恢复了结果。因此，miR-155 是妊娠免疫适应的关键调节因子，是足够的 Treg 实现强妊娠耐受和防止胎儿丢失所必需的。与 miR-155+/+ 对照相比，miR-155-/- 小鼠对炎症诱导的胎儿丢失和胎儿生长受限表现出更高的易感性，但通过转移野生型 Treg 恢复了结果。因此，miR-155 是妊娠免疫适应的关键调节因子，是足够的 Treg 实现强妊娠耐受和防止胎儿丢失所必需的。

更新日期：2020-01-27

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