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

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

CORRESPONDENCE Averil Ma: averil.ma{at}ucsf.edu

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

© 2008 Mortier et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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