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

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.

• Authors: Melissa Bedard, Dilip Shrestha, David A Priestman, Yuting Wang, Falk Schneider, Juan D Matute, Shankar S Iyer, Uzi Gileadi, Gennaro Prota, Matheswaran Kandasamy, Natacha Veerapen, Gurdyal Besra, Marco Fritzsche, Sebastian Zeissig, Andrej Shevchenko, John C Christianson, Frances M Platt, Christian Eggeling, Richard S Blumberg, Mariolina Salio, Vincenzo Cerundolo
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 116 Issue 47 Pg. 23671-23681 (11 19 2019) ISSN: 1091-6490 [Electronic] United States
• PMID: 31690657 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 the Author(s). Published by PNAS.

Chemical References

• Antigens, CD1d
• Autoantigens
• CD1D protein, human
• CD1d antigen, mouse
• Glycosphingolipids
• IL2RA protein, human
• Interleukin-2 Receptor alpha Subunit
• Lipids
• Thapsigargin
• EIF2AK3 protein, human
• eIF-2 Kinase

Topics

• Animals
• Antigen Presentation
• Antigen-Presenting Cells (immunology)
• Antigens, CD1d (biosynthesis, immunology)
• Autoantigens (immunology)
• Carcinoma, Lewis Lung (pathology)
• Cell Line, Tumor
• Coculture Techniques
• Cytoskeleton (ultrastructure)
• Dendritic Cells (immunology)
• Endoplasmic Reticulum Stress (immunology)
• Endosomes (immunology)
• Glycosphingolipids (immunology, metabolism)
• 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, physiology)