Department of Pediatrics, Division of Hematology/Oncology and Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, USA.
Am J Transplant. 2011 Jun;11(6):1148-57. doi: 10.1111/j.1600-6143.2011.03558.x. Epub 2011 May 12.
Adoptive transfer of thymus-derived natural regulatory T cells (nTregs) effectively suppresses disease in murine models of autoimmunity and graft-versus-host disease (GVHD). TGFß induces Foxp3 expression and suppressive function in stimulated murine CD4+25- T cells, and these induced Treg (iTregs), like nTreg, suppress auto- and allo-reactivity in vivo. However, while TGFß induces Foxp3 expression in stimulated human T cells, the expanded cells lack suppressor cell function. Here we show that Rapamycin (Rapa) enhances TGFß-dependent Foxp3 expression and induces a potent suppressor function in naive (CD4+ 25-45RA+) T cells. Rapa/TGFß iTregs are anergic, express CD25 at levels higher than expanded nTregs and few cells secrete IL-2, IFNγ or IL-17 even after PMA and Ionomycin stimulation in vitro. Unlike other published methods of inducing Treg function, Rapa/TGFß induces suppressive function even in the presence of memory CD4+ T cells. A single apheresis unit of blood yields an average ~240 × 10⁹ (range ~ 70-560 × 10⁹) iTregs from CD4+25- T cells in ≤ 2 weeks of culture. Most importantly, Rapa/TGFß iTregs suppress disease in a xenogeneic model of GVHD. This study opens the door for iTreg cellular therapy for human diseases.
胸腺来源的天然调节性 T 细胞（nTreg）的过继转移可有效抑制自身免疫和移植物抗宿主病（GVHD）的小鼠模型中的疾病。TGFβ可诱导刺激的小鼠 CD4+25-T 细胞中 Foxp3 的表达和抑制功能，这些诱导的调节性 T 细胞（iTreg）与 nTreg 一样，可在体内抑制自身和同种异体反应。然而，虽然 TGFβ可诱导刺激的人 T 细胞中 Foxp3 的表达，但扩增的细胞缺乏抑制细胞功能。我们发现雷帕霉素（Rapa）增强了 TGFβ依赖性 Foxp3 的表达，并在幼稚（CD4+25-45RA+）T 细胞中诱导出强大的抑制功能。Rapa/TGFβ iTreg 呈无反应状态，表达的 CD25 水平高于扩增的 nTreg，并且很少有细胞在体外经 PMA 和离子霉素刺激后分泌 IL-2、IFNγ或 IL-17。与其他已发表的诱导 Treg 功能的方法不同，即使存在记忆性 CD4+T 细胞，Rapa/TGFβ 也可诱导抑制功能。单次单采术可从 CD4+25-T 细胞中在≤2 周的培养时间内获得平均约 240×10⁹（范围~70-560×10⁹）的 iTreg。最重要的是，Rapa/TGFβ iTreg 可抑制异种移植物抗宿主病的疾病。这项研究为 iTreg 细胞疗法治疗人类疾病开辟了道路。
