Antigen-dependent suppression of alloresponses by Foxp3-induced regulatory T cells in transplantation
Antigen-dependent suppression of alloresponses by Foxp3-induced regulatory T cells in transplantation
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DOI：
10.1002/eji.200526077
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发表时间：
2005-09-01
影响因子：
5.4
通讯作者：
Yu, XZ
中科院分区：
文献类型：
--
作者：
Albert, MH;Liu, Y;Yu, XZ
过继转移多克隆CD4(+)CD25(+)调节性T细胞(Treg)可耐受移植异体反应。Treg通过其特有的TCR被激活，但野生型Treg的抗原特异性仍然难以捉摸，因此在移植环境中控制Treg活性的效力和持续时间仍然不可行。在本研究中，我们以小鼠移植物抗宿主病(GVHD)为模型系统，在体外显示抗原特异性Treg抑制T效应细胞对同种异体抗原的反应，并在体内预防GVHD。抗原特异性Treg的抑制潜能远大于多克隆Treg。为了获得大量的抗原特异性Treg，我们用Foxp3转导CD4(+)CD25(-)细胞，发现这些Foxp3诱导的Treg在体外抑制同种异体反应，在体内预防GVHD，与天然来源的CD4(+)CD25(+)Treg一样有效。此外，我们使用抗原特异性的CD4Th1克隆作为Foxp3诱导的Treg的来源，发现这些Treg以抗原依赖的方式有效地预防GVHD。本研究结果为Treg抑制免疫耐受的开始和效力可调控这一概念提供了基础，并为提高Treg作为移植过继免疫治疗诱导耐受的可行性和有效性提供了新的途径。
Adoptive transfer of polyclonal CD4(+)CD25(+) regulatory T cells (Treg) can tolerize transplantation alloresponses. Treg are activated via their specific TCR, but the antigen specificity of wild-type Treg remains elusive, and therefore controlling potency and duration of Treg activity in the transplantation setting is still not feasible. In this study, we used murine graft-versus-host disease (GVHD) as a model system to show that antigen-specific Treg suppress the response of T effector cells to alloantigens in vitro and prevent GVHD in vivo. The suppressive potential of antigen-specific Treg was much greater than that of polyclonal Treg. To acquire large numbers of antigen-specific Treg, we transduced CD4(+)CD25(-) cells with foxp3, and found that these foxp3-induced Treg suppress alloresponses in vitro and prevent GVHD in vivo as effectively as naturally derived CD4(+)CD25(+) Treg. Furthermore, we used an antigen-specific CD4 Th1 clone as a source of foxp3-induced Treg after transduction with foxp3, and found those Treg to effectively prevent GVHD in an antigen-dependent manner. The findings of this study provide a basis for the concept that the onset and potency of the suppression by Treg can be regulated, and suggest a novel approach to enhance the feasibility and effectiveness of inducing tolerance by Treg as an adoptive immunotherapy in transplantation.