ER stress in antigen‐presenting cells promotes NKT cell activation through endogenous neutral lipids. (3rd May 2020)

• Record Type: Journal Article
• Authors: Govindarajan, Srinath; Verheugen, Eveline; Venken, Koen; Gaublomme, Djoere; Maelegheer, Margaux; Cloots, Eva; Gysens, Fien; De Geest, Bruno G; Cheng, Tan‐Yun; Moody, D Branch; Janssens, Sophie; Drennan, Michael; Elewaut, Dirk
• Is Part Of: EMBO reports. Volume 21:Number 6(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-05-03
• Subjects: antigen‐presenting cells -- ER stress -- lipid antigens -- neutral lipid -- NKT cells; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201948927
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: 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. Synopsis: Upon ER stress immunogenic lipids are produced that activate NKT cells. Defining the conditions required to generate endogenous high immunogenic lipid antigens paves the way for the design of novel lipids with immunomodulatory function. ER stress triggers IRE1α/PERK pathways to restore cellular homeostasis by generating distinct neutral and polar lipids. Neutral lipid species generated under these conditions are enriched and loaded onto CD1d to activate iNKT cells. Cytokines produced by iNKT cells during ER stress serve to activate the innate and adaptive immune system. ER stress is an important mechanism to elicit endogenous CD1d‐restricted iNKT cell responses. Abstract : Upon ER stress immunogenic lipids are produced that activate NKT cells. Defining the conditions required to generate endogenous high immunogenic lipid antigens paves the way for the design of novel lipids with immunomodulatory function.