IL-15Rα chaperones IL-15 to stable dendritic cell membrane complexes that activate NK cells via trans presentation

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-15R alpha, support NK cell homeostasis in resting animals via a novel trans presentation mechanism. To better understand how IL-15 and IL-15R alpha support NK cell activation during immune responses, we have used sensitive assays for detecting native IL-15 and IL-15R alpha proteins and developed an assay for detecting complexes of these proteins. We find that IL-15 and IL-15R alpha are preassembled in complexes within the endoplasmic reticulum/Golgi of stimulated dendritic cells (DCs) before being released from cells. IL-15R alpha 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-15R alpha. We also find that soluble IL-15-IL-15R alpha complexes are induced during inflammation, but membrane-bound IL-15-IL-15R alpha complexes, rather than soluble complexes, support NK cell activation in vitro and in vivo. Finally, we provide in vivo evidence that expression of IL-15R alpha 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-15R alpha serves as a chaperone for IL-15, after which membrane-bound IL-15R alpha-IL-15 complexes activate NK cells via direct cell-cell contact.