Tuning of natural killer cell reactivity by NKp46 and Helios calibrates T cell responses.

Emilie Narni-Mancinelli (1) , Baptiste N. Jaeger (1) , Claire Bernat (2, 3, 4) , Aurore Fenis (1) , Sam Kung (5) , Aude de Gassart (1) , Sajid Mahmood (5) , Marta Gut (6, 7) , Simon C Heath (7) , Jordi Estellé (7) , Elodie Bertosio (1) , Frédéric Vely (1, 8) , Louis Noël Gastinel (9) , Bruce Beutler (10) , Bernard Malissen (1) , Marie Malissen (1) , Ivo G. Gut (7, 11) , Eric Vivier (1, 8) , Sophie Ugolini (1)

1 CIML - Centre d'Immunologie de Marseille - Luminy
2 IGR - Institut Gustave Roussy
3 VTG / UMR8121 - Vectorologie et transfert de gènes
4 UP11 - Université Paris-Sud - Paris 11
5 University of Manitoba [Winnipeg]
6 CNG - Centre National de Génotypage
7 CNAG - Centro Nacional de Análisi Genómico
8 Service de Chirurgie
9 PIST - Pharmacologie des Immunosuppresseurs et de la Transplantation
10 Department of Immunology and Microbial Science
11 Centre Nacional D'Anàlisi Genómica

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.

Domaines: Immunologie

Emilie Narni-Mancinelli, Baptiste N. Jaeger, Claire Bernat, Aurore Fenis, Sam Kung, et al.. Tuning of natural killer cell reactivity by NKp46 and Helios calibrates T cell responses.. Science, 2012, 335 (6066), pp.344-8. ⟨10.1126/science.1215621⟩. ⟨hal-00685893⟩