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

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

doi:10.1126/science.1215621

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

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

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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.

Original language	English (US)
Pages (from-to)	344-348
Number of pages	5
Journal	Science
Volume	335
Issue number	6066
DOIs	https://doi.org/10.1126/science.1215621
State	Published - Jan 20 2012

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Narni-Mancinelli, E., Jaeger, B. N., Bernat, C., Fenis, A., Kung, S., De Gassart, A., Mahmood, S., Gut, M., Heath, S. C., Estellé, J., Bertosio, E., Vely, F., Gastinel, L. N., Beutler, B., Malissen, B., Malissen, M., Gut, I. G., Vivier, E., & Ugolini, S. (2012). Tuning of natural killer cell reactivity by NKp46 and Helios calibrates T cell responses. Science, 335(6066), 344-348. https://doi.org/10.1126/science.1215621

Narni-Mancinelli, E, Jaeger, BN, Bernat, C, Fenis, A, Kung, S, De Gassart, A, Mahmood, S, Gut, M, Heath, SC, Estellé, J, Bertosio, E, Vely, F, Gastinel, LN, Beutler, B, Malissen, B, Malissen, M, Gut, IG, Vivier, E & Ugolini, S 2012, 'Tuning of natural killer cell reactivity by NKp46 and Helios calibrates T cell responses', Science, vol. 335, no. 6066, pp. 344-348. https://doi.org/10.1126/science.1215621

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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.",

author = "Emilie Narni-Mancinelli and Jaeger, {Baptiste N.} and Claire Bernat and Aurore Fenis and Sam Kung and {De Gassart}, Aude and Sajid Mahmood and Marta Gut and Heath, {Simon C.} and Jordi Estell{\'e} and Elodie Bertosio and Fr{\'e}d{\'e}ric Vely and Gastinel, {Louis N.} and Bruce Beutler and Bernard Malissen and Marie Malissen and Gut, {Ivo G.} and Eric Vivier and Sophie Ugolini",

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AU - Kung, Sam

AU - De Gassart, Aude

AU - Mahmood, Sajid

AU - Gut, Marta

AU - Heath, Simon C.

AU - Estellé, Jordi

AU - Bertosio, Elodie

AU - Vely, Frédéric

AU - Gastinel, Louis N.

AU - Beutler, Bruce

AU - Malissen, Bernard

AU - Malissen, Marie

AU - Gut, Ivo G.

AU - Vivier, Eric

AU - Ugolini, Sophie

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

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