IL-15Ralpha 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-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.
Mortier
Erwan
E
Colitis and Crohn's Disease Center, Gastroenterology Division, Department of Medicine, Biomedical Sciences Program, Program in Biological Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
Woo
Tammy
T
Advincula
Rommel
R
Gozalo
Sara
S
Ma
Averil
A
D019264:Adoptive Transfer; D000818:Animals; D002450:Cell Communication / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D019409:Interleukin-15 / Q000502:physiology*; D053720:Interleukin-15 Receptor alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit