| Summary: | 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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