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

  • Cell Rep. 2019 Dec 24;29(13):4435-4446.e9. doi: 10.1016/j.celrep.2019.11.086.
Kevin Bode  1 ,  Fatmire Bujupi  1 ,  Corinna Link  1 ,  Tobias Hein  1 ,  Stephanie Zimmermann  2 ,  Diluka Peiris  3 ,  Vincent Jaquet  4 ,  Bernd Lepenies  5 ,  Heiko Weyd  6 ,  Peter H Krammer  7
Affiliations
  • 1. Division of Immunogenetics, Research Program Immunology and Cancer, German Cancer Research Center, 69120 Heidelberg, Germany; Faculty of Biosciences, Ruprecht Karls University Heidelberg, 69120 Heidelberg, Germany.
  • 2. Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, 14476 Potsdam, Germany; Department of Biology, Chemistry and Pharmacy, Free University Berlin, 14195 Berlin, Germany.
  • 3. Attana AB, Greta Arwidssons v. 21, 11419 Stockholm, Sweden.
  • 4. Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland.
  • 5. Department 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, Germany.
  • 6. Division of Immunogenetics, Research Program Immunology and Cancer, German Cancer Research Center, 69120 Heidelberg, Germany. Electronic address: [email protected].
  • 7. Division of Immunogenetics, Research Program Immunology and Cancer, German Cancer Research Center, 69120 Heidelberg, Germany. Electronic address: [email protected].
PMID: 31875551 DOI: 10.1016/j.celrep.2019.11.086
Abstract

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.

Keywords
Dectin-1; NOX-2; SYK; annexin (A1, A5, and A13); apoptotic cells; autoimmunity; biased agonism; dendritic cells; peripheral immune tolerance; reactive oxygen species.
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