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Proc Natl Acad Sci U S A. 2019 Nov 19;116(47):23671-23681. doi: 10.1073/pnas.1910097116. Epub 2019 Nov 5.

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

Author information

1
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS Oxford, United Kingdom.
2
Department of Pharmacology, University of Oxford, OX1 3QT Oxford, United Kingdom.
3
Center for Regenerative Therapies, Technische Universität Dresden, 01307 Dresden, Germany.
4
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
5
Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital Harvard Medical School, Boston, MA 02115.
6
Division of Neonatology, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
7
School of Biosciences, University of Birmingham, B15 2TT Egdbaston, United Kingdom.
8
Kennedy Institute for Rheumatology, University of Oxford, OX3 7LF Oxford, United Kingdom.
9
Department of Medicine I, University Medical Center Dresden, Technische Universität Dresden, 01307 Dresden, Germany.
10
Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Science, University of Oxford, OX3 7LD Oxford, United Kingdom.
11
Institute of Applied Optics and Biophysics, 07743 Jena, Germany.
12
Department of Biophysical Imaging, Leibniz Institute of Photonic Technologies e.V., 07745 Jena, Germany.
13
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS Oxford, United Kingdom; vincenzo.cerundolo@imm.ox.ac.uk.

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.

KEYWORDS:

CD1d; ER stress; NKT; cancer

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