SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-{gamma} and IL-17A production.
SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-{gamma} and IL-17A production.
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DOI：
10.1084/jem.20110428
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发表时间：
2011-09-26
期刊：
影响因子：
--
通讯作者：
Yoshimura A
中科院分区：
文献类型：
--
作者：
Takahashi R;Nishimoto S;Muto G;Sekiya T;Tamiya T;Kimura A;Morita R;Asakawa M;Chinen T;Yoshimura A
SOCS1可以限制干扰素-γ和IL-17的表达，维持调节性T细胞Foxp3的表达和功能。调节性T细胞(Treg细胞)通过限制炎症反应来维持免疫平衡。SOCS1(细胞因子信号转导抑制因子1)是细胞因子信号转导的负调控因子，是Treg细胞在体内发挥抑制功能所必需的，但其具体机制尚不清楚。我们发现，即使FOXP3增强子区域的保守非编码序列2完全去甲基化，SOCS1TREG细胞仍能产生高水平的干扰素-γ，并在转移到RAG2−/−小鼠体内或在体外培养时迅速丢失FOXP3。SOCS1−/−Treg细胞表现出STAT1和STAT3的高活性。由于Foxp3在干扰素γ−/−SOCS1−/−Treg细胞中表达稳定，STAT1活性处于正常水平，提示SOCS1对干扰素-γ-STAT1信号通路的抑制是稳定表达Foxp3所必需的。但干扰素γ−/−SOCS1−/−Treg细胞较γ−/−SOCS1+/+Treg细胞具有更高的STAT3活性和更高的IL-17A(IL-17)产生，且不能抑制幼稚T细胞诱导的RAG2−/−小鼠结肠炎。体外实验表明，SOCs1Threg细胞和干扰素−/−γ−/−−/−Treg细胞产生的细胞因子分别调节抗原提呈细胞优先诱导Th1和Th17。我们认为SOCS1在Treg细胞的完整性和功能中发挥着重要作用，它分别通过维持foxp3的表达和抑制信号转导蛋白1和信号转导蛋白3驱动的干扰素-γ和IL-17的产生而发挥作用。
SOCS1 is required to restrict IFN-γ and IL-17 expression and maintain Foxp3 expression in and function of regulatory T cells. Regulatory T cells (Treg cells) maintain immune homeostasis by limiting inflammatory responses. SOCS1 (suppressor of cytokine signaling 1), a negative regulator of cytokine signaling, is necessary for the suppressor functions of Treg cells in vivo, yet detailed mechanisms remain to be clarified. We found that Socs1−/− Treg cells produced high levels of IFN-γ and rapidly lost Foxp3 when transferred into Rag2−/− mice or cultured in vitro, even though the CNS2 (conserved noncoding DNA sequence 2) in the Foxp3 enhancer region was fully demethylated. Socs1−/− Treg cells showed hyperactivation of STAT1 and STAT3. Because Foxp3 expression was stable and STAT1 activation was at normal levels in Ifnγ−/−Socs1−/− Treg cells, the restriction of IFN-γ–STAT1 signaling by SOCS1 is suggested to be necessary for stable Foxp3 expression. However, Ifnγ−/−Socs1−/− Treg cells had hyperactivated STAT3 and higher IL-17A (IL-17) production compared with Ifnγ−/−Socs1+/+ Treg cells and could not suppress colitis induced by naive T cells in Rag2−/− mice. In vitro experiments suggested that cytokines produced by Socs1−/− Treg cells and Ifnγ−/−Socs1−/− Treg cells modulated antigen-presenting cells for preferential Th1 and Th17 induction, respectively. We propose that SOCS1 plays important roles in Treg cell integrity and function by maintaining Foxp3 expression and by suppressing IFN-γ and IL-17 production driven by STAT1 and STAT3, respectively.
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影响因子：
32.4
作者：
Fontenot, JD;Rasmussen, JP;Rudensky, AY
通讯作者：
Rudensky, AY
影响因子：
4.4
作者：
Inagaki-Ohara, K;Chinen, T;Yoshimura, A
通讯作者：
Yoshimura, A
DOI：
10.1073/pnas.0811556106
发表时间：
2009-02-10
影响因子：
11.1
作者：
Komatsu, Noriko;Mariotti-Ferrandiz, Maria Encarnita;Hori, Shohei
通讯作者：
Hori, Shohei
影响因子：
32.4
作者：
Lu, Li-Fan;Thai, To-Ha;Calado, Dinis Pedro;Chaudhry, Ashutosh;Kubo, Masato;Tanaka, Kentaro;Loeb, Gabriel B.;Lee, Hana;Yoshimura, Akihiko;Rajewsky, Klaus;Rudensky, Alexander Y.
通讯作者：
Rudensky, Alexander Y.
影响因子：
2.6
作者：
Chan, H. C.;Ke, L. Y.;Yen, J. H.
通讯作者：
Yen, J. H.