Notch regulates Th17 differentiation and controls trafficking of IL-17 and metabolic regulators within Th17 cells in a context-dependent manner.
Notch regulates Th17 differentiation and controls trafficking of IL-17 and metabolic regulators within Th17 cells in a context-dependent manner.
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DOI：
10.1038/srep39117
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发表时间：
2016-12-15
影响因子：
4.6
通讯作者：
Tacchini-Cottier F
中科院分区：
文献类型：
--
作者：
Coutaz M;Hurrell BP;Auderset F;Wang H;Siegert S;Eberl G;Ho PC;Radtke F;Tacchini-Cottier F
Th17细胞在宿主防御和自身免疫中发挥重要作用。新的数据支持Notch信号在Th17细胞分化中的作用，但它是积极的还是消极的调节尚不清楚。我们在这里报道，T细胞特异性的Notch受体的缺失促进了肠道中Th17细胞的分化，并相应地增加了IL-17的分泌。同样，用OVA/CFA免疫T细胞特异性Notch突变小鼠后，Th17细胞频率也有增加。然而，在这种情况下，Th17细胞因子的分泌受到损害，并观察到IL-17在细胞内的滞留增加。在对照和Notch缺陷Th17细胞的引流淋巴结中，IL-17与CD71铁转运蛋白共定位。免疫诱导CD71在对照细胞表面表达，但在Notch缺陷的Th17细胞中不表达，表明在没有Notch信号的情况下CD71在细胞内转运有缺陷。此外，Notch受体缺陷的Th17细胞也降低了mTORC2的活性。这些数据揭示了Notch在高代谢需求时对囊泡运输的上下文依赖性影响，表明Notch信号在T细胞代谢需求和效应器功能之间的桥梁作用。总而言之，我们的发现表明，Notch信号在Th17细胞分化和效应器功能的微调中具有显著的调节作用。
Th17 cells play critical roles in host defense and autoimmunity. Emerging data support a role for Notch signaling in Th17 cell differentiation but whether it is a positive or negative regulator remains unclear. We report here that T cell-specific deletion of Notch receptors enhances Th17 cell differentiation in the gut, with a corresponding increase in IL-17 secretion. An increase in Th17 cell frequency was similarly observed following immunization of T cell specific Notch mutant mice with OVA/CFA. However, in this setting, Th17 cytokine secretion was impaired, and increased intracellular retention of IL-17 was observed. Intracellular IL-17 co-localized with the CD71 iron transporter in the draining lymph node of both control and Notch-deficient Th17 cells. Immunization induced CD71 surface expression in control, but not in Notch-deficient Th17 cells, revealing defective CD71 intracellular transport in absence of Notch signaling. Moreover, Notch receptor deficient Th17 cells had impaired mTORC2 activity. These data reveal a context-dependent impact of Notch on vesicular transport during high metabolic demand suggesting a role for Notch signaling in the bridging of T cell metabolic demands and effector functions. Collectively, our findings indicate a prominent regulatory role for Notch signaling in the fine-tuning of Th17 cell differentiation and effector function.
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DOI：
10.4049/jimmunol.1003658
发表时间：
2011-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Keerthivasan S;Suleiman R;Lawlor R;Roderick J;Bates T;Minter L;Anguita J;Juncadella I;Nickoloff BJ;Le Poole IC;Miele L;Osborne BA
通讯作者：
Osborne BA
影响因子：
64.5
作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
通讯作者：
Littman, Dan R.
影响因子：
30.5
作者：
Charbonnier LM;Wang S;Georgiev P;Sefik E;Chatila TA
通讯作者：
Chatila TA
影响因子：
15.9
作者：
Ito, Toshihiro;Schaller, Matthew;Kunkel, Steven L.
通讯作者：
Kunkel, Steven L.
影响因子：
6.7
作者：
Auderset F;Schuster S;Coutaz M;Koch U;Desgranges F;Merck E;MacDonald HR;Radtke F;Tacchini-Cottier F
通讯作者：
Tacchini-Cottier F