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Dectin-1 binding to annexins on apoptotic cells induces peripheral immune tolerance via NADPH oxidase-2

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Zimmermann,  Stephanie
Bernd Lepenies, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

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Lepenies,  Bernd
Bernd Lepenies, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

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Citation

Bode, K., Bujupi, F., Link, C., Hein, T., Zimmermann, S., Peiris, D., et al. (2019). Dectin-1 binding to annexins on apoptotic cells induces peripheral immune tolerance via NADPH oxidase-2. Cell Reports, 29(13), 4435-4446.e9. doi:10.1016/j.celrep.2019.11.086.


Cite as: http://hdl.handle.net/21.11116/0000-0005-6D4B-E
Abstract
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.