Development of Stem Cell-derived Antigen-specific Regulatory T Cells Against Autoimmunity.
Development of Stem Cell-derived Antigen-specific Regulatory T Cells Against Autoimmunity.
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DOI：
10.3791/54720
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发表时间：
2016-11-08
期刊：
影响因子：
--
通讯作者：
Song J
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文献类型：
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作者：
Haque M;Fino K;Sandhu P;Song J
自身免疫性疾病是由于免疫自身耐受性丧失而引起的。调节性T细胞（Tregs）是免疫自我耐受的重要介质。Tregs约占小鼠和人类成熟CD4+ T细胞亚群的5 - 10%，其中约1 - 2%的Tregs在外周血中循环。诱导多能干细胞（iPSCs）可以分化为功能性treg，具有用于自身免疫性疾病细胞治疗的潜力。在这里，我们提出了一种从ipsc（即iPSC-Tregs）中培养抗原（Ag）特异性Tregs的方法。该方法基于将转录因子FoxP3和ag特异性T细胞受体（TCR）整合到iPSCs中，然后在表达Notch配体delta-like (DL) 1和DL4的OP9基质细胞上分化。在体外分化后，ipsc - treg表达CD4、CD8、CD3、CD25、FoxP3和Ag特异性TCR，并能够对Ag刺激做出反应。该方法已成功应用于小鼠自身免疫性关节炎的细胞治疗。将这些ag特异性iPSC-Tregs过继转移到ag诱导的关节炎（AIA）小鼠中具有减轻关节炎症和肿胀并防止骨质流失的能力。
Autoimmune diseases arise due to the loss of immunological self-tolerance. Regulatory T cells (Tregs) are important mediators of immunologic self-tolerance. Tregs represent about 5 - 10% of the mature CD4+ T cell subpopulation in mice and humans, with about 1 - 2% of those Tregs circulating in the peripheral blood. Induced pluripotent stem cells (iPSCs) can be differentiated into functional Tregs, which have a potential to be used for cell-based therapies of autoimmune diseases. Here, we present a method to develop antigen (Ag)-specific Tregs from iPSCs (i.e., iPSC-Tregs). The method is based on incorporating the transcription factor FoxP3 and an Ag-specific T cell receptor (TCR) into iPSCs and then differentiating on OP9 stromal cells expressing Notch ligands delta-like (DL) 1 and DL4. Following in vitro differentiation, the iPSC-Tregs express CD4, CD8, CD3, CD25, FoxP3, and Ag-specific TCR and are able to respond to Ag stimulation. This method has been successfully applied to cell-based therapy of autoimmune arthritis in a murine model. Adoptive transfer of these Ag-specific iPSC-Tregs into Ag-induced arthritis (AIA)-bearing mice has the ability to reduce joint inflammation and swelling and to prevent bone loss.