Translational Research Center, Inha University School of Medicine, Incheon, Republic of Korea.
Drug Development Program, Department of Biomedical Sciences, Inha University School of Medicine, Incheon, Republic of Korea.
Sci Rep. 2017 Mar 14;7:44486. doi: 10.1038/srep44486.
Mesenchymal stem cells (MSCs) can modulate lymphocyte proliferation and function. One of the immunomodulatory functions of MSCs involves CD4CD25FoxP3 regulatory T cells (Tregs), which negatively regulate inflammatory responses. MSC-mediated Treg induction is supposed to be regulated by mechanisms requiring both soluble and cell contact-dependent factors. Although the involvement of soluble factors has been revealed, the contact-dependent mechanisms in MSC-mediated Treg induction remain unclear. We attempted to identify molecule(s) other than secreted factors that are responsible for MSC-mediated Treg induction and to uncover the underlying mechanisms. Under in vitro Treg-inducing conditions, ICOSL expression in MSCs coincided with Treg induction in co-cultures of MSCs with CD4 T cells. When cultured in a transwell plate, MSCs failed to induce Tregs. Neutralization or knockdown of ICOSL significantly reduced Tregs and their IL-10 release. ICOSL overexpression in MSCs promoted induction of functional Tregs. ICOSL-ICOS signaling promoted Treg differentiation from CD4 T cells through activation of the phosphoinositide 3-kinase-Akt pathway. MSCs primed with Interleukin-1β significantly induced Tregs through ICOSL upregulation. We demonstrated that the Treg-inducing activity of MSCs is proportionate to their basal ICOSL expression. This study provides evidence that ICOSL expression in human MSCs plays an important role in contact-dependent regulation of MSC-mediated Treg induction.
间充质干细胞 (MSCs) 可以调节淋巴细胞的增殖和功能。MSCs 的免疫调节功能之一涉及 CD4+CD25+FoxP3+调节性 T 细胞 (Tregs)，它负向调节炎症反应。MSCs 介导的 Treg 诱导被认为受到需要可溶性和细胞接触依赖性因子的机制调节。虽然已经揭示了可溶性因子的参与，但 MSCs 介导的 Treg 诱导的接触依赖性机制仍不清楚。我们试图确定除了分泌因子之外，还有哪些分子负责 MSCs 介导的 Treg 诱导，并揭示潜在的机制。在体外 Treg 诱导条件下，MSCs 中的 ICOSL 表达与 MSCs 与 CD4+T 细胞共培养中的 Treg 诱导同时发生。当在 Transwell 板中培养时，MSCs 未能诱导 Tregs。ICOSL 的中和或敲低显著减少了 Tregs 和它们的 IL-10 释放。MSCs 中 ICOSL 的过表达促进了功能性 Tregs 的诱导。ICOSL-ICOS 信号通过激活磷酸肌醇 3-激酶-Akt 途径促进 CD4+T 细胞向 Treg 分化。用白细胞介素-1β 预刺激的 MSCs 通过 ICOSL 的上调显著诱导 Tregs。我们证明了 MSCs 的 Treg 诱导活性与其基础 ICOSL 表达成正比。这项研究提供了证据，表明人 MSCs 中的 ICOSL 表达在 MSCs 介导的 Treg 诱导的接触依赖性调节中发挥重要作用。
