TY - JOUR AU - Subramanian, Manikandan AU - Hayes, Crystal D. AU - Thome, Joseph J. AU - Thorp, Edward AU - Matsushima, Glenn K. AU - Herz, Joachim AU - Farber, Donna L. AU - Liu, Kang AU - Lakshmana, Madepalli AU - Tabas, Ira T1 - An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo PY - 2014/03/03/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI72051 VL - 124 IS - 3 UR - https://doi.org/10.1172/JCI72051 SP - 1296 EP - 1308 PB - The American Society for Clinical Investigation ER -