The receptor DNGR-1 signals for phagosomal rupture to promote cross-presentation of dead-cell-associated antigens

CANTON, JOHNATHAN; BLEES, HANNA; HENRY, CONOR M.; BUCK, MICHAEL D.; SCHULZ, OLIVER; ROGERS, NEIL C.; CHILDS, ELEANOR; ZELENAY, SANTIAGO; RHYS, HEFIN; DOMART, MARIE-CHARLOTTE; COLLINSON, LUCY; ALLOATTI, ANDRES; ELLISON, CARA J.; AMIGORENA, SEBASTIAN; PAPAYANNOPOULOS, VENIZELOS; THOMAS, DAVID C.; RANDOW, FELIX; REIS E SOUSA, CAETANO

NATURE IMMUNOLOGY (PRINT)

NATURE PUBLISHING GROUP

Año: 2021 vol. 22 p. 140 - 153

1529-2908

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.