Home | Help | Feedback | Subscriptions | Archive | Search | Latest Articles

This Article Full Text Full Text (PDF, 4103K) PDF+supp data (6533K) PPT slides of all figures Supplemental Material Index Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Huntington, N. D. Articles by Di Santo, J. P. Search for Related Content PubMed PubMed Citation Articles by Huntington, N. D. Articles by Di Santo, J. P. Pubmed/NCBI databases Substance via MeSH Social Bookmarking                            What's this?

¹ Cytokine and Lymphoid Development Unit, Immunology Department, ² Institut National de la Santé et de la Recherche Médicale (INSERM) U668, ³ INSERM U883, Unité de Régulation Immunitaire et Vaccinologie, Institut Pasteur, Paris 75724, France
⁴ Academic Medical Center, University of Amsterdam, 1100 DD, Amsterdam, Netherlands
⁵ INSERM U892, Groupe de Recherche Cytokines et Récepteurs, Institut de Biologie, Nantes F-44093, France

CORRESPONDENCE N.D. Huntington: nhunting{at}pasteur.fr

The in vivo requirements for human natural killer (NK) cell development and differentiation into cytotoxic effectors expressing inhibitory receptors for self–major histocompatability complex class I (MHC-I; killer Ig-like receptors [KIRs]) remain undefined. Here, we dissect the role of interleukin (IL)-15 in human NK cell development using Rag2^–/–c^–/– mice transplanted with human hematopoietic stem cells. Human NK cell reconstitution was intrinsically low in this model because of the poor reactivity to mouse IL-15. Although exogenous human IL-15 (hIL-15) alone made little improvement, IL-15 coupled to IL-15 receptor (IL-15R) significantly augmented human NK cells. IL-15–IL-15R complexes induced extensive NK cell proliferation and differentiation, resulting in accumulation of CD16⁺KIR⁺ NK cells, which was not uniquely dependent on enhanced survival or preferential responsiveness of this subset to IL-15. Human NK cell differentiation in vivo required hIL-15 and progressed in a linear fashion from CD56^hiCD16^–KIR^– to CD56^loCD16⁺KIR^–, and finally to CD56^loCD16⁺KIR⁺. These data provide the first evidence that IL-15 trans-presentation regulates human NK cell homeostasis. Use of hIL-15 receptor agonists generates a robust humanized immune system model to study human NK cells in vivo. IL-15 receptor agonists may provide therapeutic tools to improve NK cell reconstitution after bone marrow transplants, enhance graft versus leukemia effects, and increase the pool of IL-15–responsive cells during immunotherapy strategies.

© 2009 Huntington 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/).

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

• Castillo, E. F., Stonier, S. W., Frasca, L., Schluns, K. S. (2009). Dendritic Cells Support the In Vivo Development and Maintenance of NK Cells via IL-15 Trans-Presentation. J. Immunol. 183: 4948-4956 [Abstract] [Full Text]  
• Bessard, A., Sole, V., Bouchaud, G., Quemener, A., Jacques, Y. (2009). High antitumor activity of RLI, an interleukin-15 (IL-15)-IL-15 receptor {alpha} fusion protein, in metastatic melanoma and colorectal cancer. Molecular Cancer Therapeutics 8: 2736-2745 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search