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

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Innate immune receptors on dendritic cells (DCs) typically drive immune responses.
• DNGR-1 (CLEC9A) on type 1 conventional DCs (cDC1s) recognizes F-actin on dead cells, promoting antigen cross-presentation for anti-viral and anti-cancer immunity.

Purpose of the Study:

• To investigate the molecular mechanisms underlying DNGR-1 function in cDC1s.
• To elucidate the role of a specific amino acid residue in DNGR-1 signaling and its impact on receptor activation and antigen cross-presentation.

Main Methods:

• Site-directed mutagenesis of the DNGR-1 receptor.
• In vitro assays to assess cDC1 activation.
• Evaluation of antigen cross-presentation capacity.

Main Results:

• A single amino acid substitution in DNGR-1 altered its signaling, converting it into an activating receptor but reducing antigen cross-presentation.
• The reverse mutation in the related Dectin-1 receptor impaired activation while enhancing cross-presentation.
• SHIP1 phosphatase recruitment, regulated by this residue, influences DNGR-1's functional output.

Conclusions:

• DNGR-1 exhibits a functional trade-off, prioritizing antigen cross-presentation over cDC1 activation.
• This evolved mechanism may serve to limit inflammatory responses to dead cells.
• Findings provide insights into fine-tuning immune receptor signaling for specific biological outcomes.