Interferon-γ conditioning ex vivo generates CD25+CD62L+Foxp3+ regulatory T cells that prevent allograft rejection:: Potential avenues for cellular therapy
Interferon-γ conditioning ex vivo generates CD25+CD62L+Foxp3+ regulatory T cells that prevent allograft rejection:: Potential avenues for cellular therapy
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DOI：
10.1097/tp.0b013e3181806a60
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发表时间：
2008-08-27
期刊：
影响因子：
6.2
通讯作者：
Bushell, Andrew
中科院分区：
文献类型：
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作者：
Feng, Gang;Wood, Kathryn J.;Bushell, Andrew
背景调节性T细胞（Treg）在预防自身免疫、移植物抗宿主病和移植排斥反应中起重要作用。在啮齿动物移植模型中，耐受性诱导策略可以在体内诱导移植物保护性CD 25（+）CD 4（+）Treg，但主动调节的治疗利用更可能取决于允许离体产生或选择调节细胞用作细胞疗法的方案。我们已经使用过继转移皮肤和胰岛同种异体移植模型来鉴定、开发和评估产生供体反应性、适应性Treg的离体方案。在中性条件下用同种异体抗原提呈细胞或用细胞因子修饰的CD 4（+）T细胞刺激幼稚CD 4（+）T细胞，在相同条件下再刺激，随后分析细胞因子谱、Treg特征性表型标志物和体内调节功能。未经修饰，CD 4（+）T细胞默认为Th 2表型，其特征在于显性白细胞介素-4应答，这对同种异体移植物存活极为不利。然而，添加外源性干扰素-γ抑制白细胞介素-4的产生而不引发效应子功能，诱导细胞因子信号传导抑制因子-1并导致Foxp 3和CD 62 L的上调。这些群体的产生通过天然存在的内源性Treg的存在而增强，但不依赖于天然存在的内源性Treg。最重要的是，当在体内测试调节功能时，这些细胞防止由效应T细胞介导的皮肤和胰岛同种异体移植物的排斥。这些数据揭示了干扰素-γ在离体产生Treg中的意想不到的作用，并提示了产生用于治疗用途的调节细胞的可能途径。
Background. Regulatory T cells (Treg) play important roles in preventing autoimmunity, graft-versus host disease and transplant rejection. In rodent transplant models, tolerance induction strategies can induce graft protective CD25(+)CD4(+) Treg in vivo but therapeutic exploitation of active regulation will more likely depend on protocols that allow generation or selection of regulatory cells ex vivo for use as a cellular therapy. We have used adoptive transfer skin and islet allograft models to identify, develop and evaluate ex vivo protocols that generate donor-reactive, adaptive Treg.Methods. Naive CDA CD4(+) T cells were stimulated with allogeneic antigen-presenting cell under neutral conditions or with cytokine modification, restimulated under identical conditions and subsequently analyzed for cytokine profile, phenotypic markers characteristic of Treg and in vivo regulatory function.Results. Without modification, CD4(+) T cells default to a Th2 phenotype characterized by a dominant interleukin-4 response which is profoundly detrimental to allograft survival. However, addition of exogenous interferon-gamma suppresses interleukin-4 production without priming for effector function, induces suppressor of cytokine signaling-1 and results in up-regulation of Foxp3 and CD62L. The generation of these Populations is enhanced by, but is independent of, the presence of naturally occurring endogenous Treg. Most importantly, when tested for regulatory function in vivo, these cells prevent rejection of both skin and islet allografts mediated by effector T cells.Conclusions. These data reveal an unexpected role for interferon-gamma in the generation of Treg ex vivo and suggest a possible route for the generation of regulatory cells for therapeutic use.