TLR3上调IDO调控MSCs抑制CD4+T细胞功能在治疗SLE中的作用及机制研究

Aberrant activation of T lymphocytes is critically involved in the initiation and progression of systemic lupus erythematosus (SLE). Mesenchymal stem cells (MSCs) are multipotent progenitor cells of stromal origin and exert immunoregulatory activities including suppressing the proliferation of T lymphocytes. Prior study showed that MSCs transplantation ameliorates SLE-like disease partly through suppressing CD4+ T cell proliferation, TLR3 engagement upregulates IDO expression of human umbilical cord-derived mesenchymal stem cells (UC-MSCs), and also enhances the immunosuppressive effects of UC-MSCs on CD4+ T lymphocytes. In this study, by in vitro and in vivo experiments, we attempt to explore whether IDO is the potential key factor responsible for the immunosuppressive effects of UC-MSCs on CD4+ T lymphocytes, further determine whether TLR3 engagement enhances the immunosuppressive effects on CD4+ T lymphocytes of human UC-MSCs by upregulating IDO, investigate the signaling pathway involved in the TLR3 activation in UC-MSCs, and eventually whether TLR3 activation augments the therapeutic efficacy of UC-MSCs transplantation to treat lupus-prone mice.

T淋巴细胞的异常活化在系统性红斑狼疮（SLE）的发病、发展中起重要作用。间充质干细胞（MSCs）是一类来源于基质组织的、具有免疫调节作用的多能祖细胞，可抑制T淋巴细胞的异常增殖。申请人的前期研究发现脐带MSCs（UC-MSC）移植可能通过抑制CD4＋T淋巴细胞的增殖，从而发挥对SLE的疗效；激活UC-MSCs的TLR3信号通路可以显著上调其吲哚胺-2，3-加双氧酶（IDO） mRNA表达，也可以增高其抑制CD4+T淋巴细胞增殖的功能。本项目将通过体内外实验，了解IDO是否是介导UC-MSCs对CD4+T淋巴细胞免疫抑制作用的关键分子；了解激活UC-MSCs的TLR3是否通过上调其IDO的表达而增强其抑制CD4+T淋巴细胞增殖的能力，并初步阐明其信号通路；明确激活TLR3的UC-MSCs移植是否可以增强其治疗SLE小鼠的疗效。

系统性红斑狼疮（Systemic lupus erythematosus, SLE）是一种常见的自身免疫病，主要特点是T、B细胞的异常活化和自身抗体的产生。间充质干细胞（mesenchymal stem cells, MSCs）移植治疗难治性自身免疫病是一项新技术。本研究中我们比较了Poly(I:C)刺激后的MSCs与未刺激的MSCs治疗狼疮鼠上的作用，以及两种MSCs对T细胞增殖和凋亡的作用，并且检测了不同浓度和时间段Poly(I:C)在刺激后MSCs表面免疫调节分子的表达，结果发现Poly(I:C)刺激后的MSCs与未刺激的MSCs均能显著改善狼疮鼠的病情，修复肾脏损伤，调节免疫细胞亚群失衡，但是二者疗效没有明显差别。Poly(I:C)刺激后的MSCs与未刺激的MSCs在体外能同等程度的抑制CD4+T细胞的增殖和凋亡。Poly(I:C)刺激可以显著上调MSCs上TLR3的表达，下调VEGF、TGF-β1、HGF。