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

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

doi:10.1073/pnas.1910097116

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

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 SalioVincenzo Cerundolo

Biosciences

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199 Downloads (Pure)

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.

Original language	English
Pages (from-to)	23671-23681
Number of pages	11
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	116
Issue number	47
Early online date	5 Nov 2019
DOIs	https://doi.org/10.1073/pnas.1910097116
Publication status	Published - 19 Nov 2019

Bibliographical note

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

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10.1073/pnas.1910097116Licence: Creative Commons: Attribution (CC BY)

BedardM2019SterileFinal published version, 2.67 MBLicence: Creative Commons: Attribution (CC BY)

https://doi.org/10.1073/pnas.1910097116Licence: Creative Commons: Attribution (CC BY)

Cite this

Bedard, M., Shrestha, D., Priestman, D. A., Wang, Y., Schneider, F., Matute, J. D., Iyer, S. S., Gileadi, U., Prota, G., Kandasamy, M., Veerapen, N., Besra, G., Fritzsche, M., Zeissig, S., Shevchenko, A., Christianson, J. C., Platt, F. M., Eggeling, C., Blumberg, R. S., ... Cerundolo, V. (2019). Sterile activation of invariant natural killer T cells by ER-stressed antigen-presenting cells. Proceedings of the National Academy of Sciences of the United States of America, 116(47), 23671-23681. Advance online publication. https://doi.org/10.1073/pnas.1910097116

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title = "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.",

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author = "Melissa Bedard and Dilip Shrestha and Priestman, {David A} and Yuting Wang and Falk Schneider and Matute, {Juan D} and Iyer, {Shankar S} and Uzi Gileadi and Gennaro Prota and Matheswaran Kandasamy and Natacha Veerapen and Gurdyal Besra and Marco Fritzsche and Sebastian Zeissig and Andrej Shevchenko and Christianson, {John C} and Platt, {Frances M} and Christian Eggeling and Blumberg, {Richard S} and Mariolina Salio and Vincenzo Cerundolo",

note = "Copyright {\textcopyright} 2019 the Author(s). Published by PNAS.",

year = "2019",

month = nov,

day = "19",

doi = "10.1073/pnas.1910097116",

language = "English",

volume = "116",

pages = "23671--23681",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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Bedard, M, Shrestha, D, Priestman, DA, Wang, Y, Schneider, F, Matute, JD, Iyer, SS, Gileadi, U, Prota, G, Kandasamy, M, Veerapen, N, Besra, G, Fritzsche, M, Zeissig, S, Shevchenko, A, Christianson, JC, Platt, FM, Eggeling, C, Blumberg, RS, Salio, M & Cerundolo, V 2019, 'Sterile activation of invariant natural killer T cells by ER-stressed antigen-presenting cells', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 47, pp. 23671-23681. https://doi.org/10.1073/pnas.1910097116

TY - JOUR

T1 - Sterile activation of invariant natural killer T cells by ER-stressed antigen-presenting cells

AU - Bedard, Melissa

AU - Shrestha, Dilip

AU - Priestman, David A

AU - Wang, Yuting

AU - Schneider, Falk

AU - Matute, Juan D

AU - Iyer, Shankar S

AU - Gileadi, Uzi

AU - Prota, Gennaro

AU - Kandasamy, Matheswaran

AU - Veerapen, Natacha

AU - Besra, Gurdyal

AU - Fritzsche, Marco

AU - Zeissig, Sebastian

AU - Shevchenko, Andrej

AU - Christianson, John C

AU - Platt, Frances M

AU - Eggeling, Christian

AU - Blumberg, Richard S

AU - Salio, Mariolina

AU - Cerundolo, Vincenzo

PY - 2019/11/19

Y1 - 2019/11/19

N2 - 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.

AB - 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.

KW - Animals

KW - Antigen Presentation

KW - Antigen-Presenting Cells/immunology

KW - Antigens, CD1d/biosynthesis

KW - Autoantigens/immunology

KW - Carcinoma, Lewis Lung/pathology

KW - Cell Line, Tumor

KW - Coculture Techniques

KW - Cytoskeleton/ultrastructure

KW - Dendritic Cells/immunology

KW - Endoplasmic Reticulum Stress/immunology

KW - Endosomes/immunology

KW - Glycosphingolipids/immunology

KW - Humans

KW - Interleukin-2 Receptor alpha Subunit/biosynthesis

KW - Lipids/immunology

KW - Lymphocyte Activation

KW - Lysosomes/immunology

KW - Mice

KW - Mice, Inbred C57BL

KW - Natural Killer T-Cells/immunology

KW - THP-1 Cells

KW - Thapsigargin/pharmacology

KW - Unfolded Protein Response/immunology

KW - eIF-2 Kinase/deficiency

U2 - 10.1073/pnas.1910097116

DO - 10.1073/pnas.1910097116

M3 - Article

C2 - 31690657

SN - 1091-6490

VL - 116

SP - 23671

EP - 23681

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 47

ER -

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

Abstract

Bibliographical note

Keywords

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