IFN-γ Production by Allogeneic Foxp3+ Regulatory T Cells Is Essential for Preventing Experimental Graft-versus-Host Disease
IFN-γ Production by Allogeneic Foxp3+ Regulatory T Cells Is Essential for Preventing Experimental Graft-versus-Host Disease
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DOI：
10.4049/jimmunol.1200413
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发表时间：
2012-09-15
影响因子：
4.4
通讯作者：
Prinz, Immo
中科院分区：
文献类型：
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作者：
Koenecke, Christian;Lee, Chun-Wei;Prinz, Immo
CD4(+)Foxp3（+）调节性T （Treg）细胞在Th1细胞因子环境中受到刺激时可以产生促炎细胞因子ifn - γ。在这项研究中，我们报告了Foxp3(+) Treg细胞在移植物抗宿主病（GVHD）的高度炎症模型中，以及在th1主导的细胞内细菌免疫反应中，体内容易产生ifn - γ。此外，仅在IL-12存在的情况下，通过TCR体外刺激足以诱导Treg细胞以剂量依赖的方式产生ifn - γ。移植供体Treg细胞可预防致死性GVHD；因此，我们使用该模型作为体内Treg功能的稳健读数。有趣的是，移植后50%的异体供体，而不是剩余的受体Foxp3(+) Treg细胞产生ifn - γ，这表明这种细胞因子的产生是异体抗原特异性的。这些ifn - γ产生者是稳定的Foxp3(+) Treg细胞，因为在GVHD期间转移和再分离的Treg细胞的Foxp3基因位点的甲基化分析显示一个完全去甲基化的Treg特异性去甲基化区域。接下来，我们研究了ifn - γ的产生是支持还是损害GVHD期间Treg细胞的免疫抑制功能。用特异性mAb阻断ifn - γ完全消除了供体Treg细胞的有益作用。我们可以进一步证明，只有野生型Treg细胞，而不是来自ifn - γ缺陷供体小鼠的Treg细胞，可以预防GVHD。这表明Treg细胞内在ifn - γ的产生是其保护功能所必需的。总之，我们的数据表明Foxp3(+) Treg细胞产生的ifn - γ具有必要的免疫调节功能，这是预防实验性GVHD所需的。免疫学杂志，2012,19(2):890- 896。
It is emerging that CD4(+)Foxp3(+) regulatory T (Treg) cells can produce the proinflammatory cytokine IFN-gamma when stimulated in a Th1 cytokine environment. In this study, we report that Foxp3(+) Treg cells readily produced IFN-gamma in vivo in a highly inflammatory model of graft-versus-host disease (GVHD) and during a Th1-dominated immune response to intracellular bacteria. Moreover, stimulation in vitro via TCR in the presence of IL-12 alone was sufficient to induce IFN-gamma production by Treg cells in a dose-dependent manner. Transfer of donor Treg cells can prevent lethal GVHD; therefore, we used this model as a robust readout for in vivo Treg function. Interestingly, > 50% of allogeneic donor, but not residual recipient Foxp3(+) Treg cells produced IFN-gamma after transplantation, suggesting that this cytokine production was alloantigen specific. These IFN-gamma producers were stable Foxp3(+) Treg cells because methylation analysis of the Foxp3 gene locus of transferred and reisolated Treg cells during GVHD showed a fully demethylated Treg-specific-demethylated region. Next, we addressed whether IFN-gamma production was supporting or rather impairing the immunosuppressive function of Treg cells during GVHD. Blocking of IFN-gamma with specific mAb completely abolished the beneficial effect of donor Treg cells. We could further show that only wild-type Treg cells, but not Treg cells from IFN-gamma-deficient donor mice, prevented GVHD. This indicated that Treg cell-intrinsic IFN-gamma production was required for their protective function. In conclusion, our data show that IFN-gamma produced by Foxp3(+) Treg cells has essential immune-regulatory functions that are required for prevention of experimental GVHD. The Journal of Immunology, 2012, 189: 2890-2896.