ER stress in antigen-presenting cells promotes NKT cell activation through endogenous neutral lipids
ER stress in antigen-presenting cells promotes NKT cell activation through endogenous neutral lipids
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DOI：
10.15252/embr.201948927
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发表时间：
2020-05-03
期刊：
影响因子：
7.7
通讯作者：
Elewaut, Dirk
中科院分区：
文献类型：
--
作者：
Govindarajan, Srinath;Verheugen, Eveline;Elewaut, Dirk
CD1d限制性不变自然杀伤T细胞(INKT)是常见的糖脂反应性先天T细胞亚群，对先天免疫和获得性免疫有广泛的影响。虽然已知几种微生物糖脂可以激活iNKT细胞，但导致内源性CD1d依赖的糖脂反应的细胞机制仍很不清楚。在这里，我们表明APC的内质网(ER)应激是CD1d依赖的iNKT细胞自身反应的有效诱导者。这一途径依赖于未折叠蛋白反应的两个转导分子：肌醇需要酶-1a(IRE1α)和蛋白激酶R样ER激酶(PERK)。令人惊讶的是，在经历内质网应激的APC中产生的中性而不是极性的脂质能够激活iNKT细胞。这些数据表明，内质网应激是通过诱导不同类别的中性脂类来诱导内源性CD1d限制性iNKT细胞反应的重要机制。
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 (IRE1 alpha) 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.