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：

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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。