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

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

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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 CD8á+ 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.

Original languageEnglish (US)
Pages (from-to)1296-1308
Number of pages13
JournalJournal of Clinical Investigation
Volume124
Issue number3
DOIs
StatePublished - Mar 3 2014

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Low Density Lipoprotein Receptor-Related Protein-1
Cross-Priming
Antigen Presentation
Carrier Proteins
Multiprotein Complexes
T-Lymphocytes
Self Tolerance
Cytophagocytosis
Viral Antigens
Human Herpesvirus 1
Receptor Protein-Tyrosine Kinases
Virus Diseases
Coculture Techniques
Viral Load
Vaccines
Spleen
Antigens
Survival

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Subramanian, M., Hayes, C. D., Thome, J. J., Thorp, E., Matsushima, G. K., Herz, J., ... Tabas, I. (2014). An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo. Journal of Clinical Investigation, 124(3), 1296-1308. https://doi.org/10.1172/JCI72051

An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo. / Subramanian, Manikandan; Hayes, Crystal D.; Thome, Joseph J.; Thorp, Edward; Matsushima, Glenn K.; Herz, Joachim; Farber, Donna L.; Liu, Kang; Lakshmana, Madepalli; Tabas, Ira.

In: Journal of Clinical Investigation, Vol. 124, No. 3, 03.03.2014, p. 1296-1308.

Research output: Contribution to journalArticle

Subramanian, M, Hayes, CD, Thome, JJ, Thorp, E, Matsushima, GK, Herz, J, Farber, DL, Liu, K, Lakshmana, M & Tabas, I 2014, 'An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo', Journal of Clinical Investigation, vol. 124, no. 3, pp. 1296-1308. https://doi.org/10.1172/JCI72051
Subramanian, Manikandan ; Hayes, Crystal D. ; Thome, Joseph J. ; Thorp, Edward ; Matsushima, Glenn K. ; Herz, Joachim ; Farber, Donna L. ; Liu, Kang ; Lakshmana, Madepalli ; Tabas, Ira. / An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 3. pp. 1296-1308.
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