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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} (E.V.); ugolini{at} (S.U.)

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