IL-2 controls the stability of Foxp3 expression in TGF-beta-induced Foxp3+ T cells in vivo.
IL-2 controls the stability of Foxp3 expression in TGF-beta-induced Foxp3+ T cells in vivo.
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DOI：
10.4049/jimmunol.1100061
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发表时间：
2011-06-01
期刊：
影响因子：
--
通讯作者：
Shevach EM
中科院分区：
文献类型：
--
作者：
Chen Q;Kim YC;Laurence A;Punkosdy GA;Shevach EM
TGF-β刺激naïve小鼠CD4+Foxp3−T细胞可诱导Foxp3表达和T抑制功能。然而，Foxp3在这些诱导的T调节细胞（iTreg）中的表达是不稳定的，这增加了iTreg对自身免疫性疾病治疗无效的可能性。为了分析控制iTreg中Foxp3表达稳定性的因素，我们在小鼠OT-II Foxp3- gfp敲入中生成ova特异性iTreg。在转移到正常C57BL/6小鼠后，OT-II GFP+细胞在8天内保持高水平的Foxp3表达。然而，在体内IFA中，受OVA刺激后，它们迅速失去Foxp3的表达。这种不稳定的表型与Foxp3位点treg特异性去甲基化区域（TSDR）的强烈甲基化有关。在没有抗原刺激的情况下，IL-2/抗IL-2复合物增加了转移的Foxp3+ iTreg的数量。值得注意的是，当抗原刺激iTreg时，IL-2/anti-IL-2复合物稳定了Foxp3的表达，并导致TSDR的去甲基化增强。相反，通过删除Stat5来中和IL-2或破坏其信号传导，可以降低Foxp3的表达水平，从而降低iTreg在体内的抑制功能。我们的数据表明，体外TGF-β刺激不足以使Foxp3稳定表达的T细胞印迹。体内给药IL-2可稳定Foxp3的表达，并可能被证明是使用iTreg治疗自身免疫性疾病的有价值的辅助手段。
Stimulation of naïve mouse CD4+Foxp3− T cells in the presence of TGF-β results in the induction of Foxp3 expression and T suppressor function. However, Foxp3 expression in these induced T regulatory cells (iTreg) is unstable raising the possibility that iTreg would not be useful for treatment of autoimmune diseases. To analyze the factors that control the stability of Foxp3 expression in iTreg, we generated OVA-specific iTreg from OT-II Foxp3-GFP knock in mice. Following transfer to normal C57BL/6 mice, OT-II GFP+ cells maintained high levels of Foxp3 expression for 8 days. However, they rapidly lost Foxp3 expression upon stimulation with OVA in IFA in vivo. This unstable phenotype was associated with a strong methylation of the Treg-specific demethylated region (TSDR) within the Foxp3 locus. Administration of IL-2/anti-IL-2 complexes expanded the numbers of transferred Foxp3+ iTreg in the absence of antigen challenge. Notably, when the iTreg were stimulated with antigen, treatment with IL-2/anti-IL-2 complexes stabilized Foxp3 expression and resulted in enhanced demethylation of the TSDR. Conversely, neutralization of IL-2 or disruption of its signaling by deletion of Stat5 diminished the level of Foxp3 expression resulting in decreased suppressor function of the iTreg in vivo. Our data suggest that stimulation with TGF-β in vitro is not sufficient for imprinting T cells with stable expression of Foxp3. Administration of IL-2 in vivo results in stabilization of Foxp3 expression and may prove to be a valuable adjunct for the use of iTreg for the treatment of autoimmune diseases.
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影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
DOI：
10.4049/jimmunol.0900691
发表时间：
2009-07-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
O'Gorman WE;Dooms H;Thorne SH;Kuswanto WF;Simonds EF;Krutzik PO;Nolan GP;Abbas AK
通讯作者：
Abbas AK
影响因子：
5.4
作者：
Huter, Eva N.;Punkosdy, George A.;Glass, Deborah D.;Cheng, Lily I.;Ward, Jerrold M.;Shevach, Ethan M.
通讯作者：
Shevach, Ethan M.
影响因子：
3.7
作者：
Janson PC;Winerdal ME;Marits P;Thörn M;Ohlsson R;Winqvist O
通讯作者：
Winqvist O
影响因子：
100.3
作者：
Huehn, Jochen;Polansky, Julia K.;Hamann, Alf
通讯作者：
Hamann, Alf