DR3 signaling modulates the function of Foxp3+ regulatory T cells and the severity of acute graft-versus-host disease.
DR3 signaling modulates the function of Foxp3+ regulatory T cells and the severity of acute graft-versus-host disease.
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DOI：
10.1182/blood-2016-06-723783
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发表时间：
2016-12
期刊：
影响因子：
20.3
通讯作者：
Hidekazu Nishikii;Byung-Su Kim;Y. Yokoyama;Yan Chen;J. Baker;A. Pierini;Maite Álvarez;M. Mavers-
中科院分区：
文献类型：
--
作者：
Hidekazu Nishikii;Byung-Su Kim;Y. Yokoyama;Yan Chen;J. Baker;A. Pierini;Maite Álvarez;M. Mavers-
CD4+Foxp3+调节性T细胞(Treg)是T细胞的一个亚群，对移植后的免疫系统起调节作用，增强免疫耐受性。供者来源的Treg在异基因造血干细胞移植的小鼠模型中防止致命的急性移植物抗宿主病(GVHD)的发展。我们最近证实，对供体小鼠单一处理DR3(死亡受体3，DR3)激动型抗体可导致供体来源的α扩大并预防急性移植物抗宿主病，尽管DR3信号在移植物抗宿主病中的确切作用尚未阐明。在本研究中，我们综合分析了DR3信号激活后Treg的免疫表型，证明DR3激活的Treg(DR3-Treg)具有激活/成熟表型。此外，DR3-Treg中的CD25+Foxp3+亚群在体内表现出较强的抑制作用。αDR3对受体小鼠的预防性治疗扩大了受体来源的Treg并降低了移植物抗宿主病的严重程度，而持续移植物抗宿主病小鼠的DR3激活进一步促进了供者T细胞的激活/增殖。这些数据表明，DR3信号的功能高度依赖于T细胞的激活状态。综上所述，我们的数据表明DR3信号以时间依赖的方式影响同种异体抗原暴露后Treg的功能和T细胞的激活。这些观察结果为未来使用人类DR3信号调制进行临床试验提供了重要信息，并强调了在DR3激活后T细胞激活状态对临床结果的关键影响。
CD4+Foxp3+ regulatory T cells (Treg) are a subpopulation of T cells, which regulate the immune system and enhance immune tolerance after transplantation. Donor-derived Treg prevent the development of lethal acute graft-versus-host disease (GVHD) in murine models of allogeneic hematopoietic stem cell transplantation. We recently demonstrated that a single treatment of the agonistic antibody to DR3 (death receptor 3, αDR3) to donor mice resulted in the expansion of donor-derived Treg and prevented acute GVHD, although the precise role of DR3 signaling in GVHD has not been elucidated. In this study, we comprehensively analyzed the immunophenotype of Treg after DR3 signal activation, demonstrating that DR3-activated Treg (DR3-Treg) had an activated/mature phenotype. Furthermore, the CD25+Foxp3+ subpopulation in DR3-Treg showed stronger suppressive effects in vivo. Prophylactic treatment of αDR3 to recipient mice expanded recipient-derived Treg and reduced the severity of GVHD, whereas DR3 activation in mice with ongoing GVHD further promoted donor T-cell activation/proliferation. These data suggest that the function of DR3 signaling was highly dependent on the activation status of the T cells. In conclusion, our data demonstrated that DR3 signaling affects the function of Treg and T-cell activation after alloantigen exposure in a time-dependent manner. These observations provide important information for future clinical testing using human DR3 signal modulation and highlight the critical effect of the state of T-cell activation on clinical outcomes after activation of DR3.