DNGR-1 signalling limits dendritic cell activation for optimal antigen cross-presentation
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Michael Buck Tom Castro Dopico Oliver Schulz Ana Cardoso Probir Chakravarty Nathalie Legrave Conor Henry Johnathan Canton Estelle Wu Sonia Lee Neil Rogers Enzo Poirier William Stainier Victor Bosteels Eleanor Childs James MacRae Mark Skehel Santiago Zelenay Caetano Reis e SousaAbstract
Innate immune receptors often induce activation of conventional dendritic cells (cDCs) and enhance antigen (cross-)presentation, favouring immune responses. DNGR-1 (CLEC9A), a receptor expressed by type 1 cDCs (cDC1s) and implicated in immune responses to viruses and cancer, recognises F-actin exposed on dead cell remnants and promotes cross-presentation of associated antigens. Here, we show that recruitment of phosphatase SHIP1, a process governed by a single amino acid residue adjacent to the signalling motif of the receptor, partly explains how DNGR-1 fails to trigger cDC1 activation in vitro. Substituting this residue converts DNGR-1 into an activating receptor but decreases induction of cross-presentation of dead cell-associated antigens. Introducing the reverse mutation into the related receptor Dectin-1 impairs its activation capacity while enhancing its ability to promote cross-presentation. These findings reveal a functional trade-off in receptor signalling and suggest that DNGR-1 has evolved to prioritise antigen cross-presentation over cellular activation, possibly to minimise inflammatory responses to dead cells.
Journal details
Journal
EMBO Journal
Volume
44
Issue number
23
Pages
6857-6891
Available online
Publication date
Full text links
Publisher website (DOI)
10.1038/s44318-025-00620-z
Figshare
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Europe PubMed Central
41162754
Pubmed
41162754
