Loss of suppressor of cytokine signaling 1 in helper T cells leads to defective Th17 differentiation by enhancing antagonistic effects of IFN-γ on STAT3 and Smads
Loss of suppressor of cytokine signaling 1 in helper T cells leads to defective Th17 differentiation by enhancing antagonistic effects of IFN-γ on STAT3 and Smads
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DOI：
10.4049/jimmunol.180.6.3746
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发表时间：
2008-03-15
影响因子：
4.4
通讯作者：
Yoshimura, Akihiko
中科院分区：
文献类型：
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作者：
Tanaka, Kentaro;Lehiyama, Kenji;Yoshimura, Akihiko
细胞因子信号传导抑制因子1（SOCS1）是细胞因子的一种重要负调节因子；然而，SOCS1在Th17分化中的作用尚未明确。我们构建了T细胞特异性SOCS1缺陷小鼠，发现这些小鼠对一种依赖Th17的自身免疫疾病模型——实验性自身免疫性脑脊髓炎具有极强的抵抗力。在体外，SOCS1缺陷的初始CD4(+) T细胞主要分化为Th1细胞，而很少分化为Th17细胞。在干扰素 -γ（-/-）背景下，这些表型消失，这表明SOCS1缺陷T细胞中大量的干扰素 -γ抑制了Th17分化。白细胞介素 - 6加转化生长因子 -β在野生型T细胞中增强了视黄酸受体相关孤儿受体（ROR）γt的表达并抑制了干扰素 -γ的产生，然而在SOCS1缺陷T细胞中这些作用严重受损。这些表型可以部分通过SOCS1缺陷T细胞中因过度激活的STAT1增强诱导SOCS3从而抑制STAT3来解释。此外，SOCS1缺陷T细胞对转化生长因子 -β的敏感性低得多。在SOCS1缺陷T细胞中，转化生长因子 -β对Th1分化的抑制作用受损。在有干扰素 -γ存在的情况下，转化生长因子 -β介导的Smad转录活性在SOCS1缺陷细胞中受到严重抑制。在SOCS3过表达细胞中未观察到这种转化生长因子 -β功能的受损，这表明对Smads的抑制作用不依赖于SOCS3。因此，SOCS1通过抑制干扰素 -γ对STAT3和Smads的拮抗作用对Th17分化是必需的。SOCS3的诱导可以部分解释干扰素 -γ介导的STAT3抑制，而其他机制将参与干扰素 -γ介导的Smad抑制。SOCS1缺陷T细胞对于研究STAT1介导的Th17发育抑制的分子机制将非常有用。
Suppressor of cytokine signaling 1 (SOCS1) is an important negative regulator for cytokines; however, the role of SOCS1 in Th17 differentiation has not been clarified. We generated T cell-specific SOCS1-deficient mice and found that these mice were extremely resistant to a Th17-dependent autoimmune disease model, experimental autoimmune encephalomyelitis. SOCS1-deficient naive CD4(+) T cells were predominantly differentiated into Th1 and poorly into Th17 in vitro. These phenotypes were canceled in IFN-gamma(-1-) background, suggesting that a large amount of IFN-gamma in SOCS1-deficient T cells suppressed Th17 differentiation. IL-6 plus TGF-beta enhanced retinoic acid receptor-related orphan receptor (ROR)gamma t expression and suppressed IFN-gamma production in wild-type T cells, whereas these effects were severely impaired in SOCS1-deficient T cells. These phenotypes can be partly explained by STAT3 suppression by enhanced SOCS3 induction through hyper-STAT1 activation in SOCS1-deficient T cells. In addition, SOCS1-deficient T cells were much less sensitive to TGF-beta. Suppression of Th1 differentiation by TGF-beta was impaired in SOCS1-deficient T cells. TGF-beta-mediated Smad transcriptional activity was severely inhibited in SOCS1-deficient cells in the presence of IFN-gamma. Such impairment of TGF-beta functions were not observed in SOCS3-overexpressed cells, indicating that suppression of Smads was independent of SOCS3. Therefore, SOCS1 is necessary for Th17 differentiation by suppressing antagonistic effect of IFN-gamma on both STAT3 and Smads. Induction of SOCS3 can partly explain IFN-gamma-mediated STAT3 suppression, while other mechanism(s) will be involved in IFN-gamma-mediated Smad suppression. SOCS1-deficient T cells will be very useful to investigate the molecular mechanism for the STAT1-mediated suppression of Th17 development.