Sterile activation of invariant natural killer T cells by ER-stressed antigen-presenting cells

Research output: Contribution to journalArticle

Authors

  • Melissa Bedard
  • Dilip Shrestha
  • David A Priestman
  • Yuting Wang
  • Falk Schneider
  • Juan D Matute
  • Shankar S Iyer
  • Uzi Gileadi
  • Gennaro Prota
  • Matheswaran Kandasamy
  • Marco Fritzsche
  • Sebastian Zeissig
  • Andrej Shevchenko
  • John C Christianson
  • Frances M Platt
  • Christian Eggeling
  • Richard S Blumberg
  • Mariolina Salio
  • Vincenzo Cerundolo

Colleges, School and Institutes

External organisations

  • University Laboratory of Physiology, Oxford University, Oxford, UK. ned.jenkinson@physiol.ox.ac.uk
  • Max Planck Institute of Molecular Cell Biology and Genetics
  • Harvard Medical School
  • Brigham and Women's Hospital, Harvard Medical School
  • University Medical Center Dresden
  • Leibniz Institute of Photonic Technologies e.V.

Abstract

Invariant NKT (iNKT) cells have the unique ability to shape immunity during antitumor immune responses and other forms of sterile and nonsterile inflammation. Recent studies have highlighted a variety of classes of endogenous and pathogen-derived lipid antigens that can trigger iNKT cell activation under sterile and nonsterile conditions. However, the context and mechanisms that drive the presentation of self-lipid antigens in sterile inflammation remain unclear. Here we report that endoplasmic reticulum (ER)-stressed myeloid cells, via signaling events modulated by the protein kinase RNA-like ER kinase (PERK) pathway, increase CD1d-mediated presentation of immunogenic endogenous lipid species, which results in enhanced iNKT cell activation both in vitro and in vivo. In addition, we demonstrate that actin cytoskeletal reorganization during ER stress results in an altered distribution of CD1d on the cell surface, which contributes to enhanced iNKT cell activation. These results define a previously unidentified mechanism that controls iNKT cell activation during sterile inflammation.

Bibliographic note

Copyright © 2019 the Author(s). Published by PNAS.

Details

Original languageEnglish
Pages (from-to)23671-23681
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number47
Publication statusPublished - 19 Nov 2019

Keywords

  • Animals, Antigen Presentation, Antigen-Presenting Cells/immunology, Antigens, CD1d/biosynthesis, Autoantigens/immunology, Carcinoma, Lewis Lung/pathology, Cell Line, Tumor, Coculture Techniques, Cytoskeleton/ultrastructure, Dendritic Cells/immunology, Endoplasmic Reticulum Stress/immunology, Endosomes/immunology, Glycosphingolipids/immunology, Humans, Interleukin-2 Receptor alpha Subunit/biosynthesis, Lipids/immunology, Lymphocyte Activation, Lysosomes/immunology, Mice, Mice, Inbred C57BL, Natural Killer T-Cells/immunology, THP-1 Cells, Thapsigargin/pharmacology, Unfolded Protein Response/immunology, eIF-2 Kinase/deficiency