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DNGR-1/CLEC9A signaling limits cDC1 activation to optimize crosspresentation of dead cell antigens

ABSTRACT: Innate immune receptors induce activation of conventional dendritic cells (cDCs) and enhance antigen (cross-)presentation, favoring immune responses. DNGR-1 (CLEC9A), a receptor expressed by type 1 cDCs (cDC1s) and implicated in immunity to viruses and cancers, recognizes F-actin exposed on dead cell remnants and promotes cross-presentation of associated antigens. Here, we show that DNGR-1 does not trigger cDC1 activation, in part by recruiting phosphatase SHIP1, a process governed by a single amino acid adjacent to the signaling motif of the receptor. Substituting this residue converts DNGR-1 into an activating receptor but decreases its induction of cross-presentation of dead cell-associated antigens. Interestingly, introducing the reverse mutation into related receptor Dectin-1 impairs its activation capacity while enhancing its ability to promote cross-presentation. These findings reveal an unexpected functional trade-off in receptor signaling and suggest that DNGR-1 has evolved to prioritize antigen cross-presentation over cellular activation, possibly to minimize inflammatory responses to dead cells.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Dendritic Cell

SUBMITTER: Mark Skehel

LAB HEAD: Caetano Reis e Sousa

PROVIDER: PXD059637 | Pride | 2025-10-28

REPOSITORIES: Pride

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

Project description: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.

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