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.