Aire Controls Mesenchymal Stem Cell-mediated Suppression in Chronic Colitis
Aire Controls Mesenchymal Stem Cell-mediated Suppression in Chronic Colitis
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DOI：
10.1038/mt.2011.192
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发表时间：
2012-01-01
影响因子：
12.4
通讯作者：
Turley, Shannon J.
中科院分区：
文献类型：
--
作者：
Parekkadan, Biju;Fletcher, Anne L.;Turley, Shannon J.
间充质干细胞（MSC）是一种有前途的免疫细胞，主要是基于它们在炎症和自身免疫条件下对T淋巴细胞的明显抑制。虽然MSC和T细胞之间的旁分泌串扰已经得到了很好的研究，但编程MSC进行免疫调节的内在转录开关仍然不确定。在这里，我们表明，骨髓来源的骨髓间充质干细胞需要转录调节因子Aire抑制T细胞介导的慢性结肠炎小鼠模型的发病机制。令人惊讶的是，Aire在体外并没有控制MSC对T细胞增殖的抑制。相反，Aire通过负调节促炎细胞因子早期T细胞活化因子（Eta）-1来减少T细胞线粒体还原酶。Eta-1的中和使Aire（-/-）MSC能够改善结肠炎，减少结肠中浸润效应T细胞的数量，并使T细胞还原酶水平正常化。我们认为，Aire代表了一个早期的分子开关，通过调节Eta-1来施加抑制性MSC表型。因此，监测MSC中的Aire表达可能是临床使用的关键参数。
Mesenchymal stem cells (MSCs) are emerging as a promising immunotherapeutic, based largely on their overt suppression of T lymphocytes under inflammatory and autoimmune conditions. While paracrine crosstalk between MSCs and T cells has been well-studied, an intrinsic transcriptional switch that programs MSCs for immunomodulation has remained undefined. Here we show that bone marrow-derived MSCs require the transcriptional regulator Aire to suppress T cell-mediated pathogenesis in a mouse model of chronic colitis. Surprisingly, Aire did not control MSC suppression of T cell proliferation in vitro. Instead, Aire reduced T cell mitochondrial reductase by negatively regulating a proinflammatory cytokine, early T cell activation factor (Eta)-1. Neutralization of Eta-1 enabled Aire(-/-) MSCs to ameliorate colitis, reducing the number of infiltrating effector T cells in the colon, and normalizing T cell reductase levels. We propose that Aire represents an early molecular switch imposing a suppressive MSC phenotype via regulation of Eta-1. Monitoring Aire expression in MSCs may thus be a critical parameter for clinical use.