Unit for Molecular Immunology and Inflammation, VIB Center for Inflammation Research, Technologiepark 927, 9052, Zwijnaarde (Ghent), Belgium.
Department of Rheumatology, Ghent University, Ghent University Hospital, Ghent, 9000, Belgium.
Nat Commun. 2018 Dec 17;9(1):5340. doi: 10.1038/s41467-018-07758-x.
Activated invariant natural killer T (iNKT) cells rapidly produce large amounts of cytokines, but how cytokine mRNAs are induced, stabilized and mobilized following iNKT activation is still unclear. Here we show that an endoplasmic reticulum stress sensor, inositol-requiring enzyme 1α (IRE1α), links key cellular processes required for iNKT cell effector functions in specific iNKT subsets, in which TCR-dependent activation of IRE1α is associated with downstream activation of p38 MAPK and the stabilization of preformed cytokine mRNAs. Importantly, genetic deletion of IRE1α in iNKT cells reduces cytokine production and protects mice from oxazolone colitis. We therefore propose that an IRE1α-dependent signaling cascade couples constitutive cytokine mRNA expression to the rapid induction of cytokine secretion and effector functions in activated iNKT cells.
激活的固有不变自然杀伤 T(iNKT)细胞迅速产生大量细胞因子，但 iNKT 激活后细胞因子 mRNA 是如何被诱导、稳定和转移的仍不清楚。在这里，我们发现内质网应激传感器，肌醇需求酶 1α（IRE1α），将 iNKT 细胞效应功能所需的关键细胞过程联系起来，在特定的 iNKT 亚群中，TCR 依赖性的 IRE1α 激活与下游 p38 MAPK 的激活和预先形成的细胞因子 mRNA 的稳定有关。重要的是，IRE1α 在 iNKT 细胞中的基因缺失会减少细胞因子的产生，并保护小鼠免受氧化偶氮二甲酰胺结肠炎的影响。因此，我们提出 IRE1α 依赖性信号级联将组成型细胞因子 mRNA 表达与激活的 iNKT 细胞中细胞因子分泌和效应功能的快速诱导联系起来。
