Journal
SCIENCE
Volume 335, Issue 6066, Pages 344-348Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1215621
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Funding
- European Research Council
- Functional Genomics in Mutant Mouse Models as Tools to Investigate the Complexity of Human Immunological Disease (MUGEN)
- Network of Excellence and Mechanisms
- European Union
- University of Manitoba
- Natural Sciences and Engineering Research Council
- Agence Nationale de la Recherche
- Equipe labellisee La Ligue
- Ligue Nationale contre le Cancer
- Agence pour la Recherche sur le Cancer
- Axa research fund
- INSERM
- CNRS
- Aix-Marseille University
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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.
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