TNFR-Associated Factors 2 and 5 Differentially Regulate the Instructive IL-6 Receptor Signaling Required for Th17 Development
TNFR-Associated Factors 2 and 5 Differentially Regulate the Instructive IL-6 Receptor Signaling Required for Th17 Development
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DOI：
10.4049/jimmunol.1501610
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发表时间：
2016-05-15
影响因子：
4.4
通讯作者：
So, Takanori
中科院分区：
文献类型：
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作者：
Nagashima, Hiroyuki;Okuyama, Yuko;So, Takanori
产生IL-17的CD 4（+）T细胞（Th 17细胞）调节宿主防御和免疫发病机制，IL-6在Th 17细胞的分化中起重要作用。我们以前已经确定，TNFR相关因子（TRAF）5通过C-末端TRAF结构域结合信号转导受体gp 130，并抑制IL-6介导的Th 17发育。尽管gp 130具有可被其他TRAF家族蛋白识别的TRAF结合基序，但TRAF通常如何调节IL-6驱动的Th 17分化尚不清楚。使用逆转录病毒介导的基因互补和基因沉默方法，我们发现不仅TRAF 5而且TRAF 2抑制IL-6 R信号传导，而TRAF 1，TRAF 3，TRAF 4和TRAF 6则没有。Traf 2沉默进一步促进来自Traf 5（-/-）小鼠的初始CD 4（+）T细胞分化为Th 17细胞的能力。值得注意的是，在初始CD 4（+）T细胞中表达的TRAF 5而不是TRAF 2在TCR触发后迅速下调，这表明TRAF 5在Th 17发育的初始阶段特异性抑制指导性IL-6信号。总的来说，我们的结果证明了TRAF 2和TRAF 5在IL-6介导的Th 17发育过程中的专门作用，以及TCR信号传导在TRAF 2和TRAF 5调节中的不同作用。因此，TRAF 2和TRAF 5都是Th 17发育所需的IL-6 R信号传导的重要调节剂。
IL-17-producing CD4(+) T cells (Th17 cells) regulate host defense and immune pathogenesis, and IL-6 plays an important role for the differentiation of Th17 cells. We have previously identified that TNFR-associated factor (TRAF) 5 binds to the signal-transducing receptor gp130 through the C-terminal TRAF domain and inhibits Th17 development mediated by IL-6. Although gp130 has TRAF-binding motifs that can be recognized by other TRAF family proteins, it is unclear how TRAFs regulate IL-6-driven Th17 differentiation in general. Using retrovirus-mediated gene complementation and gene silencing approaches, we found that not only TRAF5 but also TRAF2 restrained the IL-6R signaling, whereas TRAF1, TRAF3, TRAF4, and TRAF6 did not. Traf2 silencing further promoted the ability of naive CD4(+) T cells from Traf5(-/-) mice to differentiate into Th17 cells. Notably, TRAF5 but not TRAF2 expressed in naive CD4(+) T cells was rapidly downregulated after TCR triggering, which indicates that TRAF5 specifically inhibits instructive IL-6 signals in the initial stage of Th17 development. Collectively, our results demonstrate a dedicated role for TRAF2 and TRAF5 in the process of IL-6-mediated Th17 development and a differential role for TCR signaling in regulation of TRAF2 and TRAF5. Therefore, both TRAF2 and TRAF5 work as important regulators of the IL-6R signaling needed for Th17 development.