Mesenchymal stem cells (MSCs) exhibit active abilities to suppress or modulate deleterious immune responses by various molecular mechanisms. These cells are the subject of major translational efforts as cellular therapies for immune-related diseases and transplantations. Plenty of preclinical studies and clinical trials employing MSCs have shown promising safety and efficacy outcomes and also shed light on the modifications in the frequency and function of regulatory T cells (T regs). Nevertheless, the mechanisms underlying these observations are not well known. Direct cell contact, soluble factor production, and turning antigen-presenting cells into tolerogenic phenotypes, have been proposed to be among possible mechanisms by which MSCs produce an immunomodulatory environment for T reg expansion and activity. We and others demonstrated that adult bone marrow (BM)-MSCs suppress adaptive immune responses directly by inhibiting the proliferation of CD4+ helper and CD8+ cytotoxic T cells but also indirectly through the induction of T regs. In parallel, we demonstrated that fetal liver (FL)-MSCs demonstrates much longer-lasting immunomodulatory properties compared to BM-MSCs, by inhibiting directly the proliferation and activation of CD4+ and CD8+ T cells. Therefore, we investigated if FL-MSCs exert their strong immunosuppressive effect also indirectly through induction of T regs. MSCs were obtained from FL and adult BM and characterized according to their surface antigen expression, their multilineage differentiation, and their proliferation potential. Using different in vitro combinations, we performed co-cultures of FL- or BM-MSCs and murine CD3+CD25−T cells to investigate immunosuppressive effects of MSCs on T cells and to quantify their capacity to induce functional T regs. We demonstrated that although both types of MSC display similar cell surface phenotypic profile and differentiation capacity, FL-MSCs have significantly higher proliferative capacity and ability to suppress both CD4+ and CD8+ murine T cell proliferation and to modulate them towards less active phenotypes than adult BM-MSCs. Moreover, their substantial suppressive effect was associated with an outstanding increase of functional CD4+CD25+Foxp3+ T regs compared to BM-MSCs. These results highlight the immunosuppressive activity of FL-MSCs on T cells and show for the first time that one of the main immunoregulatory mechanisms of FL-MSCs passes through active and functional T reg induction.

中文翻译：

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人胎肝 MSC 的免疫抑制、免疫调节和 Foxp3+ T reg 诱导能力比成人骨髓 MSC 更有效

间充质干细胞（MSC）表现出通过各种分子机制抑制或调节有害免疫反应的主动能力。这些细胞是免疫相关疾病和移植的细胞疗法的主要转化研究对象。大量使用 MSC 的临床前研究和临床试验已显示出良好的安全性和有效性结果，并揭示了调节性 T 细胞 (T regs) 频率和功能的改变。然而，这些观察结果背后的机制尚不清楚。直接细胞接触、可溶性因子产生以及将抗原呈递细胞转化为耐受表型，已被认为是 MSC 为 T reg 扩增和活性产生免疫调节环境的可能机制之一。我们和其他人证明，成体骨髓 (BM)-MSC 通过抑制 CD4+ 辅助细胞和 CD8+ 细胞毒性 T 细胞的增殖直接抑制适应性免疫反应，同时也通过诱导 T reg 间接抑制适应性免疫反应。与此同时，我们证明，与 BM-MSC 相比，胎肝 (FL)-MSC 通过直接抑制 CD4+ 和 CD8+ T 细胞的增殖和活化而表现出更持久的免疫调节特性。因此，我们研究了 FL-MSC 是否也通过诱导 T reg 间接发挥其强大的免疫抑制作用。MSC 从 FL 和成体 BM 中获得，并根据其表面抗原表达、多谱系分化和增殖潜力进行表征。使用不同的体外组合，我们对 FL- 或 BM-MSC 与鼠 CD3+CD25−T 细胞进行共培养，以研究 MSC 对 T 细胞的免疫抑制作用，并量化其诱导功能性 T reg 的能力。我们证明，尽管两种类型的 MSC 表现出相似的细胞表面表型特征和分化能力，但 FL-MSC 具有显着更高的增殖能力和抑制 CD4+ 和 CD8+ 小鼠 T 细胞增殖并将其调节为比成人 BM- 活性较低的表型的能力。间充质干细胞。此外，与 BM-MSC 相比，它们的显着抑制作用与功能性 CD4+CD25+Foxp3+ T reg 的显着增加相关。这些结果突出了FL-MSCs对T细胞的免疫抑制活性，并首次表明FL-MSCs的主要免疫调节机制之一是通过活性和功能性Treg诱导来实现的。