Journal
CELL REPORTS
Volume 29, Issue 13, Pages 4435-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.11.086
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Funding
- German Federal Ministry of Education and Research VIP+ validation fund
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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 beta-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 systemand provide a link between immunosuppressive signals of ACs and maintenance of peripheral immune tolerance.
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