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间充质基质细胞来源的细胞外囊泡调节 CD4 T 淋巴细胞向调节表型。

Extracellular Vesicles isolated from Mesenchymal Stromal Cells Modulate CD4 T Lymphocytes Toward a Regulatory Profile.

机构信息

Departamento de Nefrologia, UNIFESP, Rua Pedro de Toledo 669, São Paulo 04039-032, Brazil.

Departamento de Imunologia, USP, Avenida Prof. Lineu Prestes 1730, ICB IV, São Paulo 05508-000, Brazil.

出版信息

Cells. 2020 Apr 23;9(4):1059. doi: 10.3390/cells9041059.

DOI:10.3390/cells9041059
PMID:32340348
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7226573/
Abstract

Mesenchymal stromal cells (MSCs) can generate immunological tolerance due to their regulatory activity in many immune cells. Extracellular vesicles (EVs) release is a pivotal mechanism by which MSCs exert their actions. In this study, we evaluate whether mesenchymal stromal cell extracellular vesicles (MSC-EVs) can modulate T cell response. MSCs were expanded and EVs were obtained by differential ultracentrifugation of the supernatant. The incorporation of MSC-EVs by T cells was detected by confocal microscopy. Expression of surface markers was detected by flow cytometry or CytoFLEX and cytokines were detected by RT-PCR, FACS and confocal microscopy and a miRNA PCR array was performed. We demonstrated that MSC-EVs were incorporated by lymphocytes in vitro and decreased T cell proliferation and Th1 differentiation. Interestingly, in Th1 polarization, MSC-EVs increased Foxp3 expression and generated a subpopulation of IFN-γ/Foxp3T cells with suppressive capacity. A differential expression profile of miRNAs in MSC-EVs-treated Th1 cells was seen, and also a modulation of one of their target genes, . MSC-EVs altered the metabolism of Th1-differentiated T cells, suggesting the involvement of the TGF-β pathway in this metabolic modulation. The addition of MSC-EVs in vivo, in an OVA immunization model, generated cells Foxp3. Thus, our findings suggest that MSC-EVs are able to specifically modulate activated T cells at an alternative regulatory profile by miRNAs and metabolism shifting.

摘要

间充质基质细胞 (MSCs) 可以通过其在许多免疫细胞中的调节活性产生免疫耐受。细胞外囊泡 (EVs) 的释放是 MSCs 发挥作用的关键机制。在这项研究中，我们评估了间充质基质细胞细胞外囊泡 (MSC-EVs) 是否可以调节 T 细胞反应。通过对上清液进行差速超速离心获得 MSC-EVs。通过共聚焦显微镜检测 T 细胞摄取 MSC-EVs 的情况。通过流式细胞术或 CytoFLEX 检测表面标志物的表达，通过 RT-PCR、FACS 和共聚焦显微镜检测细胞因子，并进行 miRNA PCR 阵列分析。我们证明 MSC-EVs 可以被体外淋巴细胞摄取，并减少 T 细胞增殖和 Th1 分化。有趣的是，在 Th1 极化中，MSC-EVs 增加了 Foxp3 的表达，并产生了具有抑制能力的 IFN-γ/Foxp3T 细胞亚群。在 MSC-EVs 处理的 Th1 细胞中观察到 miRNA 的差异表达谱，并且其靶基因之一的表达也受到调节。MSC-EVs 改变了 Th1 分化的 T 细胞的代谢，提示 TGF-β 途径参与了这种代谢调节。在 OVA 免疫模型中，体内添加 MSC-EVs 会产生 Foxp3 细胞。因此，我们的研究结果表明，MSC-EVs 通过 miRNA 和代谢转移，能够特异性调节激活的 T 细胞，使其具有替代性的调节表型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/727b/7226573/39514bfb5f22/cells-09-01059-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/727b/7226573/901204552afe/cells-09-01059-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/727b/7226573/bb22b4b53609/cells-09-01059-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/727b/7226573/bfdad37e2893/cells-09-01059-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/727b/7226573/49ffc98a11f4/cells-09-01059-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/727b/7226573/bf44f765db8b/cells-09-01059-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/727b/7226573/196018195433/cells-09-01059-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/727b/7226573/03c386dcfe46/cells-09-01059-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/727b/7226573/4f7d55d84b3d/cells-09-01059-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/727b/7226573/b10623b056a5/cells-09-01059-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/727b/7226573/39514bfb5f22/cells-09-01059-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/727b/7226573/901204552afe/cells-09-01059-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/727b/7226573/bb22b4b53609/cells-09-01059-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/727b/7226573/bfdad37e2893/cells-09-01059-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/727b/7226573/49ffc98a11f4/cells-09-01059-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/727b/7226573/bf44f765db8b/cells-09-01059-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/727b/7226573/196018195433/cells-09-01059-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/727b/7226573/03c386dcfe46/cells-09-01059-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/727b/7226573/4f7d55d84b3d/cells-09-01059-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/727b/7226573/b10623b056a5/cells-09-01059-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/727b/7226573/39514bfb5f22/cells-09-01059-g010.jpg

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