Dectin-1 Binding to Annexins on Apoptotic Cells Induces Peripheral Immune Tolerance via NADPH Oxidase-2

Summary: Uptake of apoptotic cells (ACs) by dendritic cells (DCs) and induction of a tolerogenic DC phenotype is an important mechanism for establishing peripheral tolerance to self-antigens. The receptors involved and underlying signaling pathways are not fully understood. Here, we identify Dectin-...

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Main Authors: Kevin Bode, Fatmire Bujupi, Corinna Link, Tobias Hein, Stephanie Zimmermann, Diluka Peiris, Vincent Jaquet, Bernd Lepenies, Heiko Weyd, Peter H. Krammer
Format: Article
Language:English
Published: Elsevier 2019-12-01
Series:Cell Reports
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124719315773
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author Kevin Bode
Fatmire Bujupi
Corinna Link
Tobias Hein
Stephanie Zimmermann
Diluka Peiris
Vincent Jaquet
Bernd Lepenies
Heiko Weyd
Peter H. Krammer
author_facet Kevin Bode
Fatmire Bujupi
Corinna Link
Tobias Hein
Stephanie Zimmermann
Diluka Peiris
Vincent Jaquet
Bernd Lepenies
Heiko Weyd
Peter H. Krammer
author_sort Kevin Bode
collection DOAJ
description Summary: Uptake of apoptotic cells (ACs) by dendritic cells (DCs) and induction of a tolerogenic DC phenotype is an important mechanism for establishing peripheral tolerance to self-antigens. The receptors involved and underlying signaling pathways are not fully understood. Here, we identify Dectin-1 as a crucial tolerogenic receptor binding with nanomolar affinity to the core domain of several annexins (annexin A1, A5, and A13) exposed on ACs. Annexins bind to Dectin-1 on a site distinct from the interaction site of pathogen-derived β-glucans. Subsequent tolerogenic signaling induces selective phosphorylation of spleen tyrosine kinase (SYK), causing activation of NADPH oxidase-2 and moderate production of reactive oxygen species. Thus, mice deficient for Dectin-1 develop autoimmune pathologies (autoantibodies and splenomegaly) and generate stronger immune responses (cytotoxic T cells) against ACs. Our data describe an important immunological checkpoint system and provide a link between immunosuppressive signals of ACs and maintenance of peripheral immune tolerance. : Bode et al. identify Dectin-1 on dendritic cells as a receptor for apoptotic-cell-bound annexins responsible for the induction of peripheral immune tolerance. Tolerogenic signaling depends on selective SYK phosphorylation and the production of reactive oxygen species via NADPH oxidase-2. Dectin-1-deficient mice generate stronger immune responses against apoptotic cells and develop autoimmunity. Keywords: Dectin-1, annexin (A1, A5, and A13), apoptotic cells, dendritic cells, peripheral immune tolerance, autoimmunity, SYK, NOX-2, reactive oxygen species, biased agonism
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spelling doaj.art-31132c112ccb4eda9e7c9bb04dcb514c2022-12-22T00:21:05ZengElsevierCell Reports2211-12472019-12-01291344354446.e9Dectin-1 Binding to Annexins on Apoptotic Cells Induces Peripheral Immune Tolerance via NADPH Oxidase-2Kevin Bode0Fatmire Bujupi1Corinna Link2Tobias Hein3Stephanie Zimmermann4Diluka Peiris5Vincent Jaquet6Bernd Lepenies7Heiko Weyd8Peter H. Krammer9Division of Immunogenetics, Research Program Immunology and Cancer, German Cancer Research Center, 69120 Heidelberg, Germany; Faculty of Biosciences, Ruprecht Karls University Heidelberg, 69120 Heidelberg, GermanyDivision of Immunogenetics, Research Program Immunology and Cancer, German Cancer Research Center, 69120 Heidelberg, Germany; Faculty of Biosciences, Ruprecht Karls University Heidelberg, 69120 Heidelberg, GermanyDivision of Immunogenetics, Research Program Immunology and Cancer, German Cancer Research Center, 69120 Heidelberg, Germany; Faculty of Biosciences, Ruprecht Karls University Heidelberg, 69120 Heidelberg, GermanyDivision of Immunogenetics, Research Program Immunology and Cancer, German Cancer Research Center, 69120 Heidelberg, Germany; Faculty of Biosciences, Ruprecht Karls University Heidelberg, 69120 Heidelberg, GermanyDepartment of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, 14476 Potsdam, Germany; Department of Biology, Chemistry and Pharmacy, Free University Berlin, 14195 Berlin, GermanyAttana AB, Greta Arwidssons v. 21, 11419 Stockholm, SwedenDepartment of Pathology and Immunology, University of Geneva, 1211 Geneva, SwitzerlandDepartment of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, 14476 Potsdam, Germany; Immunology Unit and Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hannover, GermanyDivision of Immunogenetics, Research Program Immunology and Cancer, German Cancer Research Center, 69120 Heidelberg, Germany; Corresponding authorDivision of Immunogenetics, Research Program Immunology and Cancer, German Cancer Research Center, 69120 Heidelberg, Germany; Corresponding authorSummary: Uptake of apoptotic cells (ACs) by dendritic cells (DCs) and induction of a tolerogenic DC phenotype is an important mechanism for establishing peripheral tolerance to self-antigens. The receptors involved and underlying signaling pathways are not fully understood. Here, we identify Dectin-1 as a crucial tolerogenic receptor binding with nanomolar affinity to the core domain of several annexins (annexin A1, A5, and A13) exposed on ACs. Annexins bind to Dectin-1 on a site distinct from the interaction site of pathogen-derived β-glucans. Subsequent tolerogenic signaling induces selective phosphorylation of spleen tyrosine kinase (SYK), causing activation of NADPH oxidase-2 and moderate production of reactive oxygen species. Thus, mice deficient for Dectin-1 develop autoimmune pathologies (autoantibodies and splenomegaly) and generate stronger immune responses (cytotoxic T cells) against ACs. Our data describe an important immunological checkpoint system and provide a link between immunosuppressive signals of ACs and maintenance of peripheral immune tolerance. : Bode et al. identify Dectin-1 on dendritic cells as a receptor for apoptotic-cell-bound annexins responsible for the induction of peripheral immune tolerance. Tolerogenic signaling depends on selective SYK phosphorylation and the production of reactive oxygen species via NADPH oxidase-2. Dectin-1-deficient mice generate stronger immune responses against apoptotic cells and develop autoimmunity. Keywords: Dectin-1, annexin (A1, A5, and A13), apoptotic cells, dendritic cells, peripheral immune tolerance, autoimmunity, SYK, NOX-2, reactive oxygen species, biased agonismhttp://www.sciencedirect.com/science/article/pii/S2211124719315773
spellingShingle Kevin Bode
Fatmire Bujupi
Corinna Link
Tobias Hein
Stephanie Zimmermann
Diluka Peiris
Vincent Jaquet
Bernd Lepenies
Heiko Weyd
Peter H. Krammer
Dectin-1 Binding to Annexins on Apoptotic Cells Induces Peripheral Immune Tolerance via NADPH Oxidase-2
Cell Reports
title Dectin-1 Binding to Annexins on Apoptotic Cells Induces Peripheral Immune Tolerance via NADPH Oxidase-2
title_full Dectin-1 Binding to Annexins on Apoptotic Cells Induces Peripheral Immune Tolerance via NADPH Oxidase-2
title_fullStr Dectin-1 Binding to Annexins on Apoptotic Cells Induces Peripheral Immune Tolerance via NADPH Oxidase-2
title_full_unstemmed Dectin-1 Binding to Annexins on Apoptotic Cells Induces Peripheral Immune Tolerance via NADPH Oxidase-2
title_short Dectin-1 Binding to Annexins on Apoptotic Cells Induces Peripheral Immune Tolerance via NADPH Oxidase-2
title_sort dectin 1 binding to annexins on apoptotic cells induces peripheral immune tolerance via nadph oxidase 2
url http://www.sciencedirect.com/science/article/pii/S2211124719315773
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