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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 February 10, 2014
Citation Information: J Clin Invest. 2014;124(3):1296-1308. https://doi.org/10.1172/JCI72051.
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Research Article Immunology

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

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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 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

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Figure 4

AXL and LRP-1 cooperate to facilitate DC efferocytosis.

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AXL and LRP-1 cooperate to facilitate DC efferocytosis.
(A and B) In viv...
(A and B) In vivo splenic DC efferocytosis was assayed in the indicated mice (n = 3 per group) 3 hours after injection of PKH67-labeled ACs. TIM-3 nAb (100 μg) was administered i.p., and GST-RAP (2 mg/mouse) was administered i.v., 30 minutes before AC injection. (C) BMDCs derived from WT or Axl–/– mice were treated with 5 μg/ml cytochalasin D to block AC internalization. To measure AC binding, cells were incubated with fluorescently labeled ACs for 1 hour in the absence or presence of 1 μg/ml GST-RAP to block LRP-1. (D) Similar to C, except the experiment was conducted in the absence of cytochalasin D to measure AC engulfment. n = 3 independent experiments. *P < 0.05 vs. respective control; #P < 0.05 vs. all other groups.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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