Unit for Molecular Immunology and Inflammation, VIB-Center for Inflammation Research, Ghent, Belgium.
Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
EMBO Rep. 2020 Jun 4;21(6):e48927. doi: 10.15252/embr.201948927. Epub 2020 May 3.
CD1d-restricted invariant natural killer T (iNKT) cells constitute a common glycolipid-reactive innate-like T-cell subset with a broad impact on innate and adaptive immunity. While several microbial glycolipids are known to activate iNKT cells, the cellular mechanisms leading to endogenous CD1d-dependent glycolipid responses remain largely unclear. Here, we show that endoplasmic reticulum (ER) stress in APCs is a potent inducer of CD1d-dependent iNKT cell autoreactivity. This pathway relies on the presence of two transducers of the unfolded protein response: inositol-requiring enzyme-1a (IRE1α) and protein kinase R-like ER kinase (PERK). Surprisingly, the neutral but not the polar lipids generated within APCs undergoing ER stress are capable of activating iNKT cells. These data reveal that ER stress is an important mechanism to elicit endogenous CD1d-restricted iNKT cell responses through induction of distinct classes of neutral lipids.
CD1d 限制性不变自然杀伤 T(iNKT)细胞构成了一种常见的糖脂反应性先天样 T 细胞亚群，对先天免疫和适应性免疫具有广泛影响。虽然已经知道几种微生物糖脂可以激活 iNKT 细胞，但导致内源性 CD1d 依赖性糖脂反应的细胞机制在很大程度上仍不清楚。在这里，我们表明 APC 中的内质网(ER)应激是 CD1d 依赖性 iNKT 细胞自身反应的有效诱导剂。该途径依赖于未折叠蛋白反应的两种转导子：肌醇需求酶 1a (IRE1α)和蛋白激酶 R 样内质网激酶(PERK)。令人惊讶的是，在经历 ER 应激的 APC 中产生的中性但不是极性脂质能够激活 iNKT 细胞。这些数据表明，ER 应激是通过诱导不同类别的中性脂质来引发内源性 CD1d 限制性 iNKT 细胞反应的重要机制。
