Lymphatic endothelial S1P promotes mitochondrial function and survival in naive T cells.
Lymphatic endothelial S1P promotes mitochondrial function and survival in naive T cells.
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DOI：
10.1038/nature22352
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发表时间：
2017-06-01
期刊：
影响因子：
64.8
通讯作者：
Schwab SR
中科院分区：
文献类型：
--
作者：
Mendoza A;Fang V;Chen C;Serasinghe M;Verma A;Muller J;Chaluvadi VS;Dustin ML;Hla T;Elemento O;Chipuk JE;Schwab SR
有效的适应性免疫反应需要大量的幼稚T细胞，这些T细胞在整个身体中迁移，快速识别几乎任何外来肽。由于T细胞的产生随着年龄的增长而下降，幼稚T细胞必须是长寿的。然而，目前尚不清楚幼稚T细胞如何在不断旅行的情况下存活多年。化学引诱物1-磷酸鞘氨醇（S1 P）引导T细胞在次级淋巴器官（包括脾脏、淋巴结和派尔集合淋巴结）中循环，T细胞在这些器官中寻找抗原。循环液中S1 P的浓度高于淋巴器官，S1 P1受体（S1 P1 R）指导T细胞从脾脏进入血液，从淋巴结和派尔集合淋巴结进入淋巴。在这里，我们表明，S1 P不仅对幼稚T细胞的循环至关重要，而且对它们的存活也至关重要。使用转基因小鼠模型，我们证明了淋巴管内皮细胞通过转运蛋白SPNS 2分泌S1 P来支持T细胞的存活，该S1 P通过T细胞上的S1 P1 R发出信号，并且对S1 P1 R的需求独立于受体在引导淋巴结退出中的既定作用。S1 P信号维持幼稚T细胞的线粒体内容物，为细胞提供能量以继续其恒定的迁移。S1 P信号通路在治疗上被靶向以抑制自身反应性T细胞运输，这些发现表明，同时靶向自身反应性或恶性细胞存活是可能的。
Effective adaptive immune responses require a large repertoire of naive T cells that migrate throughout the body, rapidly identifying almost any foreign peptide. Because the production of T cells declines with age, naive T cells must be long-lived. However, it remains unclear how naive T cells survive for years while constantly travelling. The chemoattractant sphingosine 1-phosphate (S1P) guides T cell circulation among secondary lymphoid organs, including spleen, lymph nodes and Peyer’s patches, where T cells search for antigens. The concentration of S1P is higher in circulatory fluids than in lymphoid organs, and the S1P1receptor (S1P1R) directs the exit of T cells from the spleen into blood, and from lymph nodes and Peyer’s patches into lymph. Here we show that S1P is essential not only for the circulation of naive T cells, but also for their survival. Using transgenic mouse models, we demonstrate that lymphatic endothelial cells support the survival of T cells by secreting S1P via the transporter SPNS2, that this S1P signals through S1P1R on T cells, and that the requirement for S1P1R is independent of the established role of the receptor in guiding exit from lymph nodes. S1P signalling maintains the mitochondrial content of naive T cells, providing cells with the energy to continue their constant migration. The S1P signalling pathway is being targeted therapeutically to inhibit autoreactive T cell trafficking, and these findings suggest that it may be possible simultaneously to target autoreactive or malignant cell survival.
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DOI：
10.4049/jimmunol.1200282
发表时间：
2012-07-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Nijnik A;Clare S;Hale C;Chen J;Raisen C;Mottram L;Lucas M;Estabel J;Ryder E;Adissu H;Sanger Mouse Genetics Project;Adams NC;Ramirez-Solis R;White JK;Steel KP;Dougan G;Hancock RE
通讯作者：
Hancock RE
影响因子：
16.2
作者：
Pickrell AM;Youle RJ
通讯作者：
Youle RJ
影响因子：
64.5
作者：
Chang CH;Curtis JD;Maggi LB Jr;Faubert B;Villarino AV;O'Sullivan D;Huang SC;van der Windt GJ;Blagih J;Qiu J;Weber JD;Pearce EJ;Jones RG;Pearce EL
通讯作者：
Pearce EL
DOI：
10.1073/pnas.96.18.10338
发表时间：
1999-08-31
影响因子：
11.1
作者：
Madsen, L;Labrecque, N;Fugger, L
通讯作者：
Fugger, L
影响因子：
20.3
作者：
Allende, ML;Yamashita, T;Proia, RL
通讯作者：
Proia, RL