title: 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.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University, Campus de Luminy case 906, 13288 Marseille, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Narni-Mancinelli
authors.forename: Baptiste N
authors.initials: BN
authors.lastname: Jaeger
authors.forename: Claire
authors.initials: C
authors.lastname: Bernat
authors.forename: Aurore
authors.initials: A
authors.lastname: Fenis
authors.forename: Sam
authors.initials: S
authors.lastname: Kung
authors.forename: Aude
authors.initials: A
authors.lastname: De Gassart
authors.forename: Sajid
authors.initials: S
authors.lastname: Mahmood
authors.forename: Marta
authors.initials: M
authors.lastname: Gut
authors.forename: Simon C
authors.initials: SC
authors.lastname: Heath
authors.forename: Jordi
authors.initials: J
authors.lastname: Estellé
authors.forename: Elodie
authors.initials: E
authors.lastname: Bertosio
authors.forename: Frédéric
authors.initials: F
authors.lastname: Vely
authors.forename: Louis N
authors.initials: LN
authors.lastname: Gastinel
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
authors.forename: Bernard
authors.initials: B
authors.lastname: Malissen
authors.forename: Marie
authors.initials: M
authors.lastname: Malissen
authors.forename: Ivo G
authors.initials: IG
authors.lastname: Gut
authors.forename: Eric
authors.initials: E
authors.lastname: Vivier
authors.forename: Sophie
authors.initials: S
authors.lastname: Ugolini
mesh_terms: D056704:Adaptive Immunity; D019943:Amino Acid Substitution; D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D015536:Down-Regulation; D005816:Genetic Complementation Test; D006566:Herpesviridae Infections / Q000276:immunology* / Q000821:virology; D007156:Immunologic Memory; D007694:Killer Cells, Natural / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018146:Muromegalovirus / Q000502:physiology; D016296:Mutagenesis; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D014158:Transcription, Genetic; D019562:Viral Load
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D000950:Antigens, Ly; D004268:DNA-Binding Proteins; D055627:Natural Cytotoxicity Triggering Receptor 1; C118384:Ncr1 protein, mouse; D014157:Transcription Factors; C491746:Zfpn1a2 protein, mouse