Jagged-1 is required for the expansion of CD4+ CD25+ FoxP3+ regulatory T cells and tolerogenic dendritic cells by murine mesenchymal stromal cells.
Jagged-1 is required for the expansion of CD4+ CD25+ FoxP3+ regulatory T cells and tolerogenic dendritic cells by murine mesenchymal stromal cells.
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DOI：
10.1186/s13287-015-0021-5
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发表时间：
2015-03-11
影响因子：
7.5
通讯作者：
English K
中科院分区：
文献类型：
--
作者：
Cahill EF;Tobin LM;Carty F;Mahon BP;English K
间充质基质细胞 (MSC) 具有明确的免疫调节特性，包括抑制淋巴细胞增殖和抑制树突状细胞 (DC) 成熟，涉及细胞接触和可溶性因子。这些特性使间充质干细胞成为细胞治疗的有吸引力的候选者。然而，这些特征背后的机制仍不清楚。本研究旨在探讨 MSC 诱导调节环境的机制。在存在或不存在γ分泌酶抑制剂以阻断Notch受体信号传导的情况下，将同种异体骨髓间充质基质细胞与T细胞或树突状细胞一起培养。通过流式细胞术检查 T 细胞和树突状细胞表型标记物表达的变化。生成稳定敲低的 MSC 以检查 MSC 对 Jagged 1 信号传导的影响。随后，野生型和敲低型 MSC 均被用于过敏性气道炎症动物模型体内。 Notch 配体 Jagged-1 被证明参与调节性 T 细胞 (Treg) 的 MSC 扩增。此外，MSC 诱导功能性半成熟 DC 表型，这进一步需要 Notch 信号传导来扩展 Treg。 MSC（而非 Jagged-1 敲低 MSC）可减轻过敏性气道炎症小鼠模型的病理学变化。 MSC 介导的保护作用与肺中 Treg 细胞的增强有关，并且用过敏原重新刺激的脾细胞中白细胞介素 (IL)-10 的产生显着增加。在用 Jagged-1 敲低 MSC 治疗的小鼠中观察到 Treg 和 IL-10 显着减少。目前的研究表明，MSC 介导的免疫调节涉及以 Jagged-1 依赖性方式培养和扩增调节性免疫细胞，并首次报告了 Jagged-1 信号传导在 MSC 保护体内免受炎症的重要性。本文的在线版本 (doi:10.1186/s13287-015-0021-5) 包含补充材料，可供授权用户使用。
Mesenchymal stromal cells (MSC) have well defined immunomodulatory properties including the suppression of lymphocyte proliferation and inhibition of dendritic cell (DC) maturation involving both cell contact and soluble factors. These properties have made MSC attractive candidates for cellular therapy. However, the mechanism underlying these characteristics remains unclear. This study sought to investigate the mechanisms by which MSC induce a regulatory environment. Allogeneic bone marrow mesenchymal stromal cells were cultured with T cells or dendritic cells in the presence or absence of gamma secretase inhibitor to block Notch receptor signalling. T cells and dendritic cells were examined by flow cytometry for changes in phenotype marker expression. Stable knock down MSC were generated to examine the influence of Jagged 1 signalling by MSC. Both wildtype and knockdown MSC were subsequently used in vivo in an animal model of allergic airway inflammation. The Notch ligand Jagged-1 was demonstrated to be involved in MSC expansion of regulatory T cells (Treg). Additionally, MSC-induced a functional semi-mature DC phenotype, which further required Notch signalling for the expansion of Treg. MSC, but not Jagged-1 knock down MSC, reduced pathology in a mouse model of allergic airway inflammation. Protection mediated by MSC was associated with enhanced Treg in the lung and significantly increased production of interleukin (IL)-10 in splenocytes re-stimulated with allergen. Significantly less Treg and IL-10 was observed in mice treated with Jagged-1 knock down MSC. The current study suggests that MSC-mediated immune modulation involves the education and expansion of regulatory immune cells in a Jagged-1 dependent manner and provides the first report of the importance of Jagged-1 signalling in MSC protection against inflammation in vivo. The online version of this article (doi:10.1186/s13287-015-0021-5) contains supplementary material, which is available to authorized users.
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DOI：
10.1084/jem.20110767
发表时间：
2011-09-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kendal AR;Chen Y;Regateiro FS;Ma J;Adams E;Cobbold SP;Hori S;Waldmann H
通讯作者：
Waldmann H
影响因子：
4.6
作者：
Kota DJ;DiCarlo B;Hetz RA;Smith P;Cox CS Jr;Olson SD
通讯作者：
Olson SD
影响因子：
4.4
作者：
English, Karen;Barry, Frank P.;Mahon, Bernard P.
通讯作者：
Mahon, Bernard P.
影响因子：
5.2
作者：
Djouad, Farida;Charbonnier, Louis-Marie;Noel, Daniele
通讯作者：
Noel, Daniele
影响因子：
5.4
作者：
Hill, Marcelo;Tanguy-Royer, Severine;Anegon, Ignacio
通讯作者：
Anegon, Ignacio