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.

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.

MeSH terms

  • Aging / metabolism
  • Animals
  • Annexins / chemistry
  • Annexins / metabolism*
  • Antigens / metabolism
  • Apoptosis*
  • Autoimmunity
  • Binding Sites
  • Conserved Sequence / genetics
  • Drosophila
  • Female
  • Humans
  • Immunosuppression Therapy
  • Jurkat Cells
  • Lectins, C-Type / metabolism*
  • Male
  • Mice, Knockout
  • NADPH Oxidase 2 / metabolism*
  • NF-kappa B / metabolism
  • Peripheral Tolerance*
  • Phosphorylation
  • Protein Binding
  • Protein Domains
  • Reactive Oxygen Species / metabolism
  • Syk Kinase / metabolism
  • beta-Glucans / metabolism

Substances

  • Annexins
  • Antigens
  • Lectins, C-Type
  • NF-kappa B
  • Reactive Oxygen Species
  • beta-Glucans
  • dectin 1
  • NADPH Oxidase 2
  • Syk Kinase