An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo

J Clin Invest. 2014 Mar;124(3):1296-308. doi: 10.1172/JCI72051. Epub 2014 Feb 10.

Abstract

The phagocytosis of apoptotic cells (ACs), or efferocytosis, by DCs is critical for self-tolerance and host defense. Although many efferocytosis-associated receptors have been described in vitro, the functionality of these receptors in vivo has not been explored in depth. Using a spleen efferocytosis assay and targeted genetic deletion in mice, we identified a multiprotein complex--composed of the receptor tyrosine kinase AXL, LDL receptor-related protein-1 (LRP-1), and RAN-binding protein 9 (RANBP9)--that mediates DC efferocytosis and antigen cross-presentation. We found that AXL bound ACs, but required LRP-1 to trigger internalization, in murine CD8α+ DCs and human-derived DCs. AXL and LRP-1 did not interact directly, but relied on RANBP9, which bound both AXL and LRP-1, to form the complex. In a coculture model of antigen presentation, the AXL/LRP-1/RANBP9 complex was used by DCs to cross-present AC-associated antigens to T cells. Furthermore, in a murine model of herpes simplex virus-1 infection, mice lacking DC-specific LRP-1, AXL, or RANBP9 had increased AC accumulation, defective viral antigen-specific CD8+ T cell activation, enhanced viral load, and decreased survival. The discovery of this multiprotein complex that mediates functionally important DC efferocytosis in vivo may have implications for future studies related to host defense and DC-based vaccines.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Antigen Presentation
  • Apoptosis*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / virology
  • Coculture Techniques
  • Cross-Priming*
  • Cytoskeletal Proteins / metabolism*
  • Dendritic Cells / physiology*
  • Female
  • Hepatitis A Virus Cellular Receptor 2
  • Herpesviridae Infections / immunology
  • Herpesviridae Infections / pathology
  • Herpesvirus 1, Human / immunology
  • Humans
  • Jurkat Cells
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiprotein Complexes / metabolism
  • Nuclear Proteins / metabolism*
  • Phagocytosis
  • Protein Binding
  • Proto-Oncogene Proteins / metabolism*
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptors, LDL / metabolism*
  • Receptors, Virus / metabolism
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytoskeletal Proteins
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Lrp1 protein, mouse
  • Multiprotein Complexes
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Ran binding protein 9
  • Receptors, LDL
  • Receptors, Virus
  • Tumor Suppressor Proteins
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase