The Journal of Experimental Medicine
Cytokines Montreal 2008
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Published online May 5, 2008
doi:10.1084/jem.20071913
The Journal of Experimental Medicine
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Mortier et al.
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ARTICLE

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

Erwan Mortier, Tammy Woo, Rommel Advincula, Sara Gozalo, and Averil Ma

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{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.

Abbreviations used: BMDC, bone Marrow–derived DC; DT, diphtheria toxin; HSC, hematopoietic stem cell; poly I:C, poly inosinic–polycytidylic acid; TLR, Toll-like receptor.


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