2. Academic Validation
  3. DNGR-1 signalling limits dendritic cell activation for optimal antigen cross-presentation

DNGR-1 signalling limits dendritic cell activation for optimal antigen cross-presentation

  • EMBO J. 2025 Oct 29. doi: 10.1038/s44318-025-00620-z.
Michael D Buck 1,  Tomás Castro-Dopico 2,  Oliver Schulz 2,  Ana Cardoso 2 3,  Probir Chakravarty 4,  Nathalie Legrave 5 6,  Conor M Henry 2 7,  Johnathan Canton 2 8,  Estelle Wu 2,  Sonia Lee 2,  Neil C Rogers 2,  Enzo Z Poirier 2 9,  William Stainier 2,  Victor Bosteels 2,  Eleanor Childs 2,  James I MacRae 5,  J Mark Skehel 10,  Santiago Zelenay 11,  Caetano Reis E Sousa 12
Affiliations

Affiliations

  • 1 Immunobiology Laboratory, The Francis Crick Institute, London, UK. michael.buck@crick.ac.uk.
  • 2 Immunobiology Laboratory, The Francis Crick Institute, London, UK.
  • 3 Medical Department, ADM Health & Wellness, London, UK.
  • 4 Bioinformatics and Biostatistics, The Francis Crick Institute, London, UK.
  • 5 Metabolomics, The Francis Crick Institute, London, UK.
  • 6 Metabolomics Platform, Luxembourg Institute of Health, Strassen, Luxembourg.
  • 7 Roche Products Ltd., Welwyn Garden City, UK.
  • 8 Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada.
  • 9 Innate Immunity in Physiology and Cancer Laboratory, Institut Curie, PSL Research University, INSERM, Paris, France.
  • 10 Proteomics, The Francis Crick Institute, London, UK.
  • 11 Cancer Inflammation and Immunity Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK.
  • 12 Immunobiology Laboratory, The Francis Crick Institute, London, UK. caetano@crick.ac.uk.
PMID: 41162754 DOI: 10.1038/s44318-025-00620-z
Abstract

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.

Keywords

Activation; CLEC9A; Cross-presentation; DNGR-1; cDC1.

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