The role of CD4+CD25+T cells for immunological tolerance induction in organ transplantation

在胸腺中选择CD4+CD25+调节性T细胞，控制自身反应性胸腺逃逸，防止单纯负选择或缺失无法实现的自身免疫，在维持免疫稳态中发挥重要作用。CD4+CD25+调节性T细胞不仅在预防自身免疫方面具有重要意义，还被证明参与器官移植中的同种异体移植物耐受。最近的研究表明，Foxp3是CD4+CD25+调节性T细胞发育的关键调控基因，其编码forkhead转录调控家族成员Scurfin。我们之前已经引入了两种HLA I类转基因小鼠，这对阐明HLA I类分子在移植生物学中的作用很有价值。本研究使用异位心脏移植模型，我们发现胸腺内接种供体HLA I类衍生的合成肽导致移植物浸润淋巴细胞Foxp3水平升高和血管化异体移植物的接受。此外，我们通过过继性转移实验证明，在胸腺内接种合成肽后获得的CD4+CD25+调节性T细胞有效地诱导移植物特异性耐受，而无需对受体进行预处理或使用额外的免疫抑制药物。该研究为CD4+CD25+治疗提供了适用于临床移植的新选择。

CD4+CD25+ regulatory T cells are selected in the thymus to control autoreactive thymic escapees preventing autoimmunity that can not be achieved by negative selection or deletion alone, thus playing an important role in the maintenance of immunological homeostasis. Not only significant in preventing autoimmunity, CD4+CD25+ regulatory T cells have also been shown to be involved in allograft tolerance in organ transplantation. Recent studies suggest that Foxp3, which encodes Scurfin, a member of the forkhead family of transcriptional regulators, is the key regulatory gene for the development of CD4+CD25+ regulatory T cells. We have formerly introduced two lines of HLA class I transgenic mice valuable to elucidate the role of HLA class I molecules in transplantation biology. Here, using a heterotopic cardiac transplantation model, we show that intrathymic inoculation of donor HLA class I derived synthetic peptide results in elevation of Foxp3 level in graft infiltrating lymphocytes and acceptance of the vascularized allograft. In addition, we demonstrate by adoptive transfer experiments that CD4+CD25+ regulatory T cells obtained following intrathymic inoculation of the synthetic peptide effectively induce graft specific tolerance without preconditioning of the recipient or use of additional immunosuppressive drugs. The study provides evidence suggestive of novel therapeutic option with CD4+CD25+ applicable to clinical transplantation.