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

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.

• Authors: Emilie Narni-Mancinelli, Baptiste N Jaeger, Claire Bernat, Aurore Fenis, Sam Kung, Aude De Gassart, Sajid Mahmood, Marta Gut, Simon C Heath, Jordi Estellé, Elodie Bertosio, Frédéric Vely, Louis N Gastinel, Bruce Beutler, Bernard Malissen, Marie Malissen, Ivo G Gut, Eric Vivier, Sophie Ugolini
• Journal: Science (New York, N.Y.) (Science) Vol. 335 Issue 6066 Pg. 344-8 (Jan 20 2012) ISSN: 1095-9203 [Electronic] United States
• PMID: 22267813 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Blocking
• Antibodies, Monoclonal
• Antigens, Ly
• DNA-Binding Proteins
• Natural Cytotoxicity Triggering Receptor 1
• Ncr1 protein, mouse
• Transcription Factors
• Zfpn1a2 protein, mouse

Topics

• Adaptive Immunity
• Amino Acid Substitution
• Animals
• Antibodies, Blocking (immunology)
• Antibodies, Monoclonal (immunology)
• Antigens, Ly (genetics, immunology, physiology)
• CD8-Positive T-Lymphocytes (immunology)
• Cell Line
• DNA-Binding Proteins (genetics, physiology)
• Down-Regulation
• Genetic Complementation Test
• Herpesviridae Infections (immunology, virology)
• Immunologic Memory
• Killer Cells, Natural (immunology)
• Listeriosis (immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Muromegalovirus (physiology)
• Mutagenesis
• Natural Cytotoxicity Triggering Receptor 1 (antagonists & inhibitors, genetics, immunology, physiology)
• T-Lymphocytes (immunology)
• Transcription Factors (genetics, physiology)
• Transcription, Genetic
• Viral Load