Journal
EMBO REPORTS
Volume 21, Issue 6, Pages -Publisher
WILEY
DOI: 10.15252/embr.201948927
Keywords
antigen-presenting cells; ER stress; lipid antigens; neutral lipid; NKT cells
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Funding
- Fund for Scientific Research-Flanders (FWO)
- Group-ID Multidisciplinary Platform (MRP) of Ghent University
- Fund for Scientific Research-Flanders
- Stichting tegen Kanker, Belgium
- NIH [R01 AR048632]
- Excellence of Science (EOS) Grant
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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.
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