DNGR-1 signalling limits dendritic cell activation for optimal antigen cross-presentation
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.
Authors
- Michael D. Buck (ORCID: https://orcid.org/0000-0002-9611-1199)
- Johnathan Canton (ORCID: https://orcid.org/0000-0001-8869-8404)
- Nathalie Legrave (ORCID: https://orcid.org/0000-0003-1172-4955)
- Mark Skehel (ORCID: https://orcid.org/0000-0002-2432-0901)
- Eleanor Childs (ORCID: https://orcid.org/0000-0002-1167-8672)
- Santiago Zelenay (ORCID: https://orcid.org/0000-0002-6865-3978)
- Victor Bosteels (ORCID: https://orcid.org/0000-0001-8838-021X)
- Caetano Reis e Sousa (ORCID: https://orcid.org/0000-0001-7392-2119)
- Probir Chakravarty (ORCID: https://orcid.org/0000-0003-1146-8824)
- Estelle Wu (ORCID: https://orcid.org/0000-0002-6197-6694)
- Sonia Lee
- Enzo Z. Poirier (ORCID: https://orcid.org/0000-0001-9795-2144)
- Oliver Schulz (ORCID: https://orcid.org/0000-0002-1493-3341)
- Neil C. Rogers (ORCID: https://orcid.org/0000-0001-8977-7585)
- Ana Cardoso (ORCID: https://orcid.org/0000-0002-4610-4337)
- Tomas Castro‐Dopico (ORCID: https://orcid.org/0000-0002-6964-5478)
- James I. MacRae (ORCID: https://orcid.org/0000-0002-1464-8583)
- Conor M. Henry (ORCID: https://orcid.org/0000-0001-7504-5121)
- William Stainier (ORCID: https://orcid.org/0009-0003-6182-4003)
Institutions
- Department of Health and Social Care (GB)
- Inserm (FR)
- University of Calgary (CA)
- Université Paris Sciences et Lettres (FR)
- The Francis Crick Institute (GB)
- Luxembourg Institute of Health (LU)
- Immunité et Cancer (FR)
- Roche (United Kingdom) (GB)
- Cancer Research UK Manchester Institute (GB)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2025-10-29
- DOI
- https://doi.org/10.1038/s44318-025-00620-z
- Citations
- 1
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 0.80