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

Nat Immunol. 2021 Feb;22(2):140-153. doi: 10.1038/s41590-020-00824-x. Epub 2020 Dec 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation*
  • Cell Death
  • Coculture Techniques
  • Cross-Priming*
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism*
  • HEK293 Cells
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Lectins, C-Type / genetics
  • Lectins, C-Type / metabolism*
  • Ligands
  • Mice
  • NADPH Oxidases / metabolism
  • Phagosomes / genetics
  • Phagosomes / immunology
  • Phagosomes / metabolism*
  • Phosphorylation
  • RAW 264.7 Cells
  • Reactive Oxygen Species / metabolism
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Receptors, Mitogen / genetics
  • Receptors, Mitogen / metabolism*
  • Signal Transduction
  • Syk Kinase / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*

Substances

  • CLEC9a protein, human
  • Clec9a protein, mouse
  • Histocompatibility Antigens Class I
  • Lectins, C-Type
  • Ligands
  • Reactive Oxygen Species
  • Receptors, Immunologic
  • Receptors, Mitogen
  • NADPH Oxidases
  • SYK protein, human
  • Syk Kinase
  • Syk protein, mouse