IL-15Ralpha chaperones IL-15 to stable dendritic cell membrane complexes that activate NK cells via trans presentation
Graduate School of Biomedical Sciences; Colitis and Crohn's Disease Center
Medical Subject Headings
Adoptive Transfer; Animals; Cell Communication; Cell Membrane; Dendritic Cells; Enzyme-Linked Immunosorbent Assay; Interleukin-15; Interleukin-15 Receptor alpha Subunit; Killer Cells, Natural; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Knockout
Life Sciences | Medicine and Health Sciences
Natural killer (NK) cells are innate immune effectors that mediate rapid responses to viral antigens. Interleukin (IL)-15 and its high affinity IL-15 receptor, IL-15Ralpha, support NK cell homeostasis in resting animals via a novel trans presentation mechanism. To better understand how IL-15 and IL-15Ralpha support NK cell activation during immune responses, we have used sensitive assays for detecting native IL-15 and IL-15Ralpha proteins and developed an assay for detecting complexes of these proteins. We find that IL-15 and IL-15Ralpha are preassembled in complexes within the endoplasmic reticulum/Golgi of stimulated dendritic cells (DCs) before being released from cells. IL-15Ralpha is required for IL-15 production by DCs, and IL-15 that emerges onto the cell surface of matured DCs does not bind to neighboring cells expressing IL-15Ralpha. We also find that soluble IL-15-IL-15Ralpha complexes are induced during inflammation, but membrane-bound IL-15-IL-15Ralpha complexes, rather than soluble complexes, support NK cell activation in vitro and in vivo. Finally, we provide in vivo evidence that expression of IL-15Ralpha specifically on DCs is critical for trans presenting IL-15 and activating NK cells. These studies define an unprecedented cytokine-receptor biosynthetic pathway in which IL-15Ralpha serves as a chaperone for IL-15, after which membrane-bound IL-15Ralpha-IL-15 complexes activate NK cells via direct cell-cell contact.
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Citation: J Exp Med. 2008 May 12;205(5):1213-25. Epub 2008 May 5. Link to article on publisher's site
The Journal of experimental medicine
Mortier, Erwan; Woo, Tammy; Advincula, Rommel; Gozalo, Sara; and Ma, Averil, "IL-15Ralpha chaperones IL-15 to stable dendritic cell membrane complexes that activate NK cells via trans presentation" (2008). GSBS Student Publications. 1497.