1. Sterile activation of invariant natural killer T cells by ER-stressed antigen-presenting cells
- Author
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Marco Fritzsche, Melissa Bedard, Gurdyal S. Besra, Dilip Shrestha, Frances M. Platt, Christian Eggeling, Mariolina Salio, Sebastian Zeissig, Shankar S. Iyer, David A. Priestman, Uzi Gileadi, Yuting Wang, Vincenzo Cerundolo, Andrej Shevchenko, Matheswaran Kandasamy, Gennaro Prota, John C. Christianson, Richard S. Blumberg, Falk Schneider, Natacha Veerapen, and Juan D. Matute
- Subjects
0301 basic medicine ,THP-1 Cells ,Cell ,Lymphocyte Activation ,Autoantigens ,Carcinoma, Lewis Lung ,Mice ,eIF-2 Kinase ,0302 clinical medicine ,Immunology and Inflammation ,Cytoskeleton ,Antigen Presentation ,Multidisciplinary ,biology ,Chemistry ,NKT ,Biological Sciences ,Endoplasmic Reticulum Stress ,Lipids ,3. Good health ,Cell biology ,medicine.anatomical_structure ,PNAS Plus ,030220 oncology & carcinogenesis ,CD1D ,Thapsigargin ,Cell activation ,ER stress ,Antigen-Presenting Cells ,Endosomes ,CD1d ,Glycosphingolipids ,03 medical and health sciences ,Immune system ,Cell Line, Tumor ,medicine ,cancer ,Animals ,Humans ,Protein kinase A ,Antigen-presenting cell ,Endoplasmic reticulum ,Interleukin-2 Receptor alpha Subunit ,Dendritic Cells ,Coculture Techniques ,Mice, Inbred C57BL ,030104 developmental biology ,Unfolded protein response ,biology.protein ,Unfolded Protein Response ,Natural Killer T-Cells ,Antigens, CD1d ,Lysosomes - Abstract
Significance While there is a clear understanding of how invariant NKT (iNKT) cells are activated in foreign infection, it remains unclear how they are activated during sterile inflammation, including cancer, where they have a well-defined role in tumor immunosurveillance. Here we elucidate a mechanism by which iNKT cells are activated through 1) the presentation of self-lipid antigens by endoplasmic reticulum-stressed antigen-presenting cells and 2) enhanced functional avidity driven by actin cytoskeletal remodeling. We further provide evidence that this mechanism of activation is at play in tumor settings. Here we describe a physiological context, relevant to human health and disease, that drives the presentation of immunogenic self-lipids to activate iNKT cells during sterile inflammation., 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.
- Published
- 2019