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<p>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&#xa0;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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月29日

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  • Michael D Buck,
  • Tomás Castro-Dopico,
  • Oliver Schulz,
  • Ana Cardoso,
  • Probir Chakravarty,
  • Nathalie Legrave,
  • Conor M Henry,
  • Johnathan Canton,
  • Estelle Wu,
  • Sonia Lee,
  • Neil C Rogers,
  • Enzo Z Poirier,
  • William Stainier,
  • Victor Bosteels,
  • Eleanor Childs,
  • James I MacRae,
  • J Mark Skehel,
  • Santiago Zelenay,
  • Caetano Reis e Sousa

摘要

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.