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Calcium signals regulate the functional differentiation of thymic iNKT cells
The EMBO Journal ( IF 9.4 ) Pub Date : 2021-06-25 , DOI: 10.15252/embj.2021107901
Meng Zhao 1, 2, 3 , Ariel Quintana 4, 5 , Chen Zhang 4 , Alexander Y Andreyev 6 , William Kiosses 7 , Tomomi Kuwana 8 , Anne Murphy 9 , Patrick G Hogan 4, 10 , Mitchell Kronenberg 1, 11
Affiliation  

How natural or innate-like lymphocytes generate the capacity to produce IL-4 and other cytokines characteristic of type 2 immunity remains unknown. Invariant natural killer T (iNKT) cells differentiate in the thymus into NKT1, NKT2, and NKT17 subsets, similar to mature, peripheral CD4+ T helper cells. The mechanism for this differentiation was not fully understood. Here, we show that NKT2 cells required higher and prolonged calcium (Ca2+) signals and continuing activity of the calcium release-activated calcium (CRAC) channel, than their NKT1 counterparts. The sustained Ca2+ entry via CRAC pathway in NKT2 cells was apparently mediated by ORAI and controlled in part by the large mitochondrial Ca2+ uptake. Unique properties of mitochondria in NKT2 cells, including high activity of oxidative phosphorylation, may regulate mitochondrial Ca2+ buffering in NKT2 cells. In addition, the low Ca2+ extrusion rate may also contribute to the higher Ca2+ level in NKT2 cells. Altogether, we identified ORAI-dependent Ca2+ signaling connected with mitochondria and cellular metabolism, as a central regulatory pathway for the differentiation of NKT2 cells.

中文翻译:


钙信号调节胸腺 iNKT 细胞的功能分化



天然或先天样淋巴细胞如何产生产生 IL-4 和 2 型免疫特征的其他细胞因子的能力仍不清楚。恒定自然杀伤 T (iNKT) 细胞在胸腺中分化为 NKT1、NKT2 和 NKT17 子集,类似于成熟的外周 CD4 + T 辅助细胞。这种分化的机制尚不完全清楚。在这里,我们表明,与 NKT1 细胞相比,NKT2 细胞需要更高和更长的钙 (Ca 2+ ) 信号以及钙释放激活钙 (CRAC) 通道的持续活性。 NKT2 细胞中通过 CRAC 途径的持续 Ca 2+进入显然是由 ORAI 介导的,并且部分由大量线粒体 Ca 2+摄取控制。 NKT2 细胞中线粒体的独特特性(包括高活性的氧化磷酸化)可能调节 NKT2 细胞中的线粒体 Ca 2+缓冲。此外,低Ca 2+挤出率也可能导致NKT2细胞中较高的Ca 2+水平。总而言之,我们确定了与线粒体和细胞代谢相关的 ORAI 依赖性 Ca 2+信号传导,作为 NKT2 细胞分化的中心调节途径。
更新日期:2021-08-16
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