Canton, Blees, and Henry et al. showed that DNGR-1 (also called CLEC9A), a cDC1 receptor for dead-cell debris, promoted ligand uptake and independently provoked irreversible damage to phagosome membranes and efflux of phagosomal contents into the cytosol. In the cytosol, dead cell-associated antigens underwent MHC I pathway processing for cross-presentation to CD8+ T cells. Stimulation of phagosomal damage mapped to DNGR-1’s intracellular signalling domain, which acted even when grafted onto other receptors and in other cell types. Phagosomal damage was mediated by SYK induction of a local NADPH-dependent oxidative burst.
Contributed by Paula Hochman
ABSTRACT: Type 1 conventional dendritic (cDC1) cells are necessary for cross-presentation of many viral and tumor antigens to CD8(+) T cells. cDC1 cells can be identified in mice and humans by high expression of DNGR-1 (also known as CLEC9A), a receptor that binds dead-cell debris and facilitates XP of corpse-associated antigens. Here, we show that DNGR-1 is a dedicated XP receptor that signals upon ligand engagement to promote phagosomal rupture. This allows escape of phagosomal contents into the cytosol, where they access the endogenous major histocompatibility complex class I antigen processing pathway. The activity of DNGR-1 maps to its signaling domain, which activates SYK and NADPH oxidase to cause phagosomal damage even when spliced into a heterologous receptor and expressed in heterologous cells. Our data reveal the existence of innate immune receptors that couple ligand binding to endocytic vesicle damage to permit MHC class I antigen presentation of exogenous antigens and to regulate adaptive immunity.
Author Info: (1) Immunobiology Laboratory, The Francis Crick Institute, London, UK. (2) Immunobiology Laboratory, The Francis Crick Institute, London, UK. (3) Immunobiology Laboratory, The Fran
Author Info: (1) Immunobiology Laboratory, The Francis Crick Institute, London, UK. (2) Immunobiology Laboratory, The Francis Crick Institute, London, UK. (3) Immunobiology Laboratory, The Francis Crick Institute, London, UK. (4) Immunobiology Laboratory, The Francis Crick Institute, London, UK. (5) Immunobiology Laboratory, The Francis Crick Institute, London, UK. (6) Immunobiology Laboratory, The Francis Crick Institute, London, UK. (7) Immunobiology Laboratory, The Francis Crick Institute, London, UK. (8) Cancer Inflammation and Immunity Group, CRUK Manchester Institute, The University of Manchester, Alderley Park, UK. (9) Flow Cytometry STP, The Francis Crick Institute, London, UK. (10) Electron Microscopy STP, The Francis Crick Institute, London, UK. (11) Electron Microscopy STP, The Francis Crick Institute, London, UK. (12) Centre de Recherche, INSERM U932, Institut Curie, Paris, France. (13) Antimicrobial Defence Laboratory, The Francis Crick Institute, London, UK. Immunity and Inflammation, 9NC, Imperial College, London, UK. (14) Centre de Recherche, INSERM U932, Institut Curie, Paris, France. (15) MRC Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Hills Road, Cambridge, UK. (16) Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. (17) Antimicrobial Defence Laboratory, The Francis Crick Institute, London, UK. Immunity and Inflammation, 9NC, Imperial College, London, UK. (18) Immunobiology Laboratory, The Francis Crick Institute, London, UK. caetano@crick.ac.uk.
