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
  • 1. Immunobiology Laboratory, The Francis Crick Institute, London, UK. [email protected].
  • 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. [email protected].
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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