iPSC-Derived Regulatory Dendritic Cells Inhibit Allograft Rejection by Generating Alloantigen-Specific Regulatory T Cells.
iPSC-Derived Regulatory Dendritic Cells Inhibit Allograft Rejection by Generating Alloantigen-Specific Regulatory T Cells.
复制标题
iPSC 衍生的调节性树突细胞通过生成同种异体抗原特异性调节性 T 细胞来抑制同种异体移植排斥
DOI：
10.1016/j.stemcr.2017.03.020
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发表时间：
2017-05-09
影响因子：
5.9
通讯作者：
Li XK
中科院分区：
文献类型：
--
作者：
Cai S;Hou J;Fujino M;Zhang Q;Ichimaru N;Takahara S;Araki R;Lu L;Chen JM;Zhuang J;Zhu P;Li XK
基于调节性树突细胞（DCregs）的免疫疗法是移植排斥的潜在治疗工具。我们从小鼠诱导多能干细胞（iPSC）中产生了 DCreg，即使在强烈刺激下，它也能保持在“稳定的未成熟阶段”。利用这一特性，我们假设 iPS-DCregs 作为阴性疫苗来产生调节性 T 细胞 (Treg)，并诱导供体特异性同种异体移植物接受。我们用 B6 (H-2Kb) iPS-DCregs 对初始 CBA (H-2Kk) 小鼠进行免疫，发现 CBA 脾细胞中的 Tregs (CD4+CD25+FOXP3+) 显着增加。此外，免疫 CBA 受者以供体特异性模式永久接受 B6 心脏移植物。我们从机制上证明了供体型 iPS-DCregs 触发了转化生长因子 β1 的分泌，在此过程中供体抗原肽引导幼稚 CD4+ T 细胞在体内分化为供体特异性 FOXP3+ Tregs，而不是分化为效应 T 细胞。这些发现凸显了 iPS-DCregs 作为临床移植中关键细胞治疗资源的潜力。 iPS-DCregs 保持稳定的未成熟阶段，使其成为强大的细胞疫苗 供体型 iPS-DCregs 导致同种异体心脏移植物的永久接受 iPS-DCregs 减少 CTL 并下调促炎细胞因子 iPS-DCregs 以 TGF-β1 依赖性方式增强 Tregs 迁移能力 在本文中，Li 及其同事从小鼠 iPSC 中生成了 DCregs，并从机制上证明了供体型 iPS-DCregs 触发TGF-β1 分泌，供体抗原肽引导幼稚 CD4+ T 细胞在体内分化为供体特异性 Tregs，而不是分化为 Teff。这些发现凸显了 iPS-DCregs 作为临床移植中关键细胞治疗资源的潜力。
Regulatory dendritic cell (DCregs)-based immunotherapy is a potential therapeutic tool for transplant rejection. We generated DCregs from murine induced pluripotent stem cells (iPSCs), which could remain in a “stable immature stage” even under strong stimulation. Harnessing this characteristic, we hypothesized that iPS-DCregs worked as a negative vaccine to generate regulatory T cells (Tregs), and induced donor-specific allograft acceptance. We immunized naive CBA (H-2Kk) mice with B6 (H-2Kb) iPS-DCregs and found that Tregs (CD4+CD25+FOXP3+) significantly increased in CBA splenocytes. Moreover, immunized CBA recipients permanently accepted B6 cardiac grafts in a donor-specific pattern. We demonstrated mechanistically that donor-type iPS-DCregs triggered transforming growth factor β1 secretion, under which the donor-antigen peptides directed naive CD4+ T cells to differentiate into donor-specific FOXP3+ Tregs instead of into effector T cells in vivo. These findings highlight the potential of iPS-DCregs as a key cell therapy resource in clinical transplantation. iPS-DCregs keep in stable immature stage that makes them a powerful cellular vaccine Donor-type iPS-DCregs lead to permanent acceptance of allogeneic cardiac grafts iPS-DCregs reduce CTL and downregulate proinflammatory cytokine iPS-DCregs enhance Tregs transmigration capability in a TGF-β1-dependent manner In this article, Li and colleagues generated DCregs from murine iPSCs and demonstrated mechanistically that donor-type iPS-DCregs triggered TGF-β1 secretion, under which the donor-antigen peptides directed naive CD4+ T cells to differentiate into donor-specific Tregs instead of into Teffs in vivo. These findings highlight the potential of iPS-DCregs as a key cell therapy resource in clinical transplantation.