Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 335 (6066): 344-348

Copyright © 2012 by the American Association for the Advancement of Science

Tuning of Natural Killer Cell Reactivity by NKp46 and Helios Calibrates T Cell Responses

Emilie Narni-Mancinelli,1,2,3 Baptiste N. Jaeger,1,2,3 Claire Bernat,1,2,3 Aurore Fenis,1,2,3 Sam Kung,4 Aude De Gassart,1,2,3 Sajid Mahmood,4 Marta Gut,5 Simon C. Heath,5 Jordi Estellé,5 Elodie Bertosio,1,2,3 Frédéric Vely,1,2,3,8 Louis N. Gastinel,6 Bruce Beutler,7 Bernard Malissen,1,2,3 Marie Malissen,1,2,3 Ivo G. Gut,5 Eric Vivier,1,2,3,8,* Sophie Ugolini1,2,3,9,*

Abstract: Natural killer (NK) cells are lymphocytes involved in antimicrobial and antitumoral immune responses. Using N-ethyl-N-nitrosourea mutagenesis in mice, we identified a mutant with increased resistance to viral infections because of the presence of hyperresponsive NK cells. Whole-genome sequencing and functional analysis revealed a loss-of-function mutation in the Ncr1 gene encoding the activating receptor NKp46. The down-regulation of NK cell activity by NKp46 was associated with the silencing of the Helios transcription factor in NK cells. NKp46 was critical for the subsequent development of antiviral and antibacterial T cell responses, which suggests that the regulation of NK cell function by NKp46 allows for the optimal development of adaptive immune responses. NKp46 blockade enhanced NK cell reactivity in vivo, which could enable the design of immunostimulation strategies in humans.

1 Centre d’Immunologie de Marseille-Luminy, Aix-Marseille University, Campus de Luminy case 906, 13288 Marseille, France.
2 INSERM U1104, 13288 Marseille, France.
3 CNRS, UMR7280, 13288 Marseille, France.
4 Apotex Center, Department of Immunology, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada.
5 Centre Nacional d'Anàlisi Genòmica (CNAG), Parc Científic de Barcelona, 08028 Barcelona, Spain.
6 INSERM U850, University of Limoges, University Hospital Limoges, 87060 Limoges, France.
7 Center for Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
8 Assistance Publique—Hôpitaux de Marseille, Hôpital de la Conception, 13385 Marseille, France.
9 Institut Paoli-Calmettes, Centre de Lutte Contre le Cancer, 13273 Marseille, France.

* To whom correspondence should be addressed. E-mail: vivier{at}ciml.univ-mrs.fr (E.V.); ugolini{at}ciml.univ-mrs.fr (S.U.)


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
TGF-{beta}-inducible microRNA-183 silences tumor-associated natural killer cells.
S. S. Donatelli, J.-M. Zhou, D. L. Gilvary, E. A. Eksioglu, X. Chen, W. D. Cress, E. B. Haura, M. B. Schabath, D. Coppola, S. Wei, et al. (2014)
PNAS 111, 4203-4208
   Abstract »    Full Text »    PDF »
The paradox of NKp46+ natural killer cells: drivers of severe hepatitis C virus-induced pathology but in-vivo resistance to interferon {alpha} treatment.
T. Pembroke, A. Christian, E. Jones, R. K. Hills, E. C. Y. Wang, A. M. Gallimore, and A. Godkin (2014)
Gut 63, 515-524
   Abstract »    Full Text »    PDF »
A Genetic Defect in Mice That Impairs Missing Self Recognition Despite Evidence for Normal Maturation and MHC Class I-Dependent Education of NK Cells.
S. L. Wickstrom, L. Oberg, K. Karre, and M. H. Johansson (2014)
J. Immunol. 192, 1577-1586
   Abstract »    Full Text »    PDF »
Utilization of mouse models to decipher natural killer cell biology and potential clinical applications.
C. M. Sungur and W. J. Murphy (2013)
Hematology 2013, 227-233
   Abstract »    Full Text »    PDF »
Natural killer cells and their receptors in multiple sclerosis.
G. Kaur, J. Trowsdale, and L. Fugger (2013)
Brain 136, 2657-2676
   Abstract »    Full Text »    PDF »
Characterization of a novel NKG2D and NKp46 double-mutant mouse reveals subtle variations in the NK cell repertoire.
S. Sheppard, C. Triulzi, M. Ardolino, D. Serna, L. Zhang, D. H. Raulet, and N. Guerra (2013)
Blood 121, 5025-5033
   Abstract »    Full Text »    PDF »
Helios marks strongly autoreactive CD4+ T cells in two major waves of thymic deletion distinguished by induction of PD-1 or NF-{kappa}B.
S. R. Daley, D. Y. Hu, and C. C. Goodnow (2013)
J. Exp. Med. 210, 269-285
   Abstract »    Full Text »    PDF »
Super-resolution imaging of remodeled synaptic actin reveals different synergies between NK cell receptors and integrins.
A. C. N. Brown, I. M. Dobbie, J.-M. Alakoskela, I. Davis, and D. M. Davis (2012)
Blood 120, 3729-3740
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882