Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews...
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • Allergy (Apr 2019)
    • Biology of familial cancer predisposition syndromes (Feb 2019)
    • Mitochondrial dysfunction in disease (Aug 2018)
    • Lipid mediators of disease (Jul 2018)
    • Cellular senescence in human disease (Apr 2018)
    • View all review series...
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Scientific Show Stoppers
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • About
  • Editors
  • Consulting Editors
  • For authors
  • Current issue
  • Past issues
  • By specialty
  • Subscribe
  • Alerts
  • Advertise
  • Contact
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • Brief Reports
  • Technical Advances
  • Commentaries
  • Editorials
  • Hindsight
  • Review series
  • Reviews
  • The Attending Physician
  • First Author Perspectives
  • Scientific Show Stoppers
  • Top read articles
  • Concise Communication
An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo
Manikandan Subramanian, … , Madepalli Lakshmana, Ira Tabas
Manikandan Subramanian, … , Madepalli Lakshmana, Ira Tabas
Published March 3, 2014; First published February 10, 2014
Citation Information: J Clin Invest. 2014;124(3):1296-1308. https://doi.org/10.1172/JCI72051.
View: Text | PDF
Categories: Research Article Immunology

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

  • Text
  • PDF
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.

Authors

Manikandan Subramanian, Crystal D. Hayes, Joseph J. Thome, Edward Thorp, Glenn K. Matsushima, Joachim Herz, Donna L. Farber, Kang Liu, Madepalli Lakshmana, Ira Tabas

×

Figure 2

Screening for DC efferocytosis receptors in vivo.

Options: View larger image (or click on image) Download as PowerPoint
Screening for DC efferocytosis receptors in vivo.
(A) In vivo splenic DC...
(A) In vivo splenic DC efferocytosis assay conducted 3 hours after injection of ACs in control mice and mice with absent or inhibited candidate efferocytosis receptors (n = 3 per group). The y axis represents the proportion of ACs engulfed by splenic CD8α+ DCs. LRP-1 was inhibited by i.v. injection of GST-RAP (2 mg/mouse), and TIM-3 was inhibited by i.p. injection of an anti–TIM-3 nAb (RMT3-23; 100 μg/mouse). (B and C) Flow cytometric quantification of the percentage of total DCs (CD11chi) and CD8α+ DCs in the spleens of the indicated mice (n = 3 per group). (D–F) Flow cytometric analysis of expression of AXL (D), LRP-1 (E), and TIM-3 (F) in CD8α+ and CD8α– splenic DCs of WT mice. *P < 0.05 vs. respective control.
Follow JCI:
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts