Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells

Priyanka Sathe; Rebecca B. Delconte; Fernando Souza-Fonseca-Guimaraes; Cyril Seillet; Michael Chopin; Cassandra J. Vandenberg; Lucille C. Rankin; Lisa A. Mielke; Ingela Vikstrom; Tatiana B. Kolesnik; Sandra E. Nicholson; Eric Vivier; Mark J. Smyth; Stephen L. Nutt; Stefan P. Glaser; Andreas Strasser; Gabrielle T. Belz; Sebastian Carotta; Nicholas D. Huntington

doi:10.1038/ncomms5539

Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells

Priyanka Sathe, Rebecca B. Delconte, Fernando Souza-Fonseca-Guimaraes, Cyril Seillet, Michael Chopin, Cassandra J. Vandenberg, Lucille C. Rankin, Lisa A. Mielke, Ingela Vikstrom, Tatiana B. Kolesnik, Sandra E. Nicholson, Eric Vivier, Mark J. Smyth, Stephen L. Nutt, Stefan P. Glaser, Andreas Strasser, Gabrielle T. Belz, Sebastian Carotta, Nicholas D. Huntington

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Abstract

The cytokine IL-15 is required for natural killer (NK) cell homeostasis; however, the intrinsic mechanism governing this requirement remains unexplored. Here we identify the absolute requirement for myeloid cell leukaemia sequence-1 (Mcl1) in the sustained survival of NK cells in vivo. Mcl1 is highly expressed in NK cells and regulated by IL-15 in a dose-dependent manner via STAT5 phosphorylation and subsequent binding to the 3'-UTR of Mcl1. Specific deletion of Mcl1 in NK cells results in the absolute loss of NK cells from all tissues owing to a failure to antagonize pro-apoptotic proteins in the outer mitochondrial membrane. This NK lymphopenia results in mice succumbing to multiorgan melanoma metastases, being permissive to allogeneic transplantation and being resistant to toxic shock following polymicrobial sepsis challenge. These results clearly demonstrate a non-redundant pathway linking IL-15 to Mcl1 in the maintenance of NK cells and innate immune responses in vivo.

Original language	English
Article number	4539
Number of pages	10
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5539
Publication status	Published - 14 Aug 2014
Externally published	Yes

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Sathe, P., Delconte, R. B., Souza-Fonseca-Guimaraes, F., Seillet, C., Chopin, M., Vandenberg, C. J., Rankin, L. C., Mielke, L. A., Vikstrom, I., Kolesnik, T. B., Nicholson, S. E., Vivier, E., Smyth, M. J., Nutt, S. L., Glaser, S. P., Strasser, A., Belz, G. T., Carotta, S., & Huntington, N. D. (2014). Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells. Nature Communications, 5, Article 4539. https://doi.org/10.1038/ncomms5539

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title = "Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells",

abstract = "The cytokine IL-15 is required for natural killer (NK) cell homeostasis; however, the intrinsic mechanism governing this requirement remains unexplored. Here we identify the absolute requirement for myeloid cell leukaemia sequence-1 (Mcl1) in the sustained survival of NK cells in vivo. Mcl1 is highly expressed in NK cells and regulated by IL-15 in a dose-dependent manner via STAT5 phosphorylation and subsequent binding to the 3'-UTR of Mcl1. Specific deletion of Mcl1 in NK cells results in the absolute loss of NK cells from all tissues owing to a failure to antagonize pro-apoptotic proteins in the outer mitochondrial membrane. This NK lymphopenia results in mice succumbing to multiorgan melanoma metastases, being permissive to allogeneic transplantation and being resistant to toxic shock following polymicrobial sepsis challenge. These results clearly demonstrate a non-redundant pathway linking IL-15 to Mcl1 in the maintenance of NK cells and innate immune responses in vivo.",

author = "Priyanka Sathe and Delconte, {Rebecca B.} and Fernando Souza-Fonseca-Guimaraes and Cyril Seillet and Michael Chopin and Vandenberg, {Cassandra J.} and Rankin, {Lucille C.} and Mielke, {Lisa A.} and Ingela Vikstrom and Kolesnik, {Tatiana B.} and Nicholson, {Sandra E.} and Eric Vivier and Smyth, {Mark J.} and Nutt, {Stephen L.} and Glaser, {Stefan P.} and Andreas Strasser and Belz, {Gabrielle T.} and Sebastian Carotta and Huntington, {Nicholas D.}",

year = "2014",

month = aug,

day = "14",

doi = "10.1038/ncomms5539",

language = "English",

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journal = "Nature Communications",

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Sathe, P, Delconte, RB, Souza-Fonseca-Guimaraes, F, Seillet, C, Chopin, M, Vandenberg, CJ, Rankin, LC, Mielke, LA, Vikstrom, I, Kolesnik, TB, Nicholson, SE, Vivier, E, Smyth, MJ, Nutt, SL, Glaser, SP, Strasser, A, Belz, GT, Carotta, S & Huntington, ND 2014, 'Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells', Nature Communications, vol. 5, 4539. https://doi.org/10.1038/ncomms5539

TY - JOUR

T1 - Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells

AU - Sathe, Priyanka

AU - Delconte, Rebecca B.

AU - Souza-Fonseca-Guimaraes, Fernando

AU - Seillet, Cyril

AU - Chopin, Michael

AU - Vandenberg, Cassandra J.

AU - Rankin, Lucille C.

AU - Mielke, Lisa A.

AU - Vikstrom, Ingela

AU - Kolesnik, Tatiana B.

AU - Nicholson, Sandra E.

AU - Vivier, Eric

AU - Smyth, Mark J.

AU - Nutt, Stephen L.

AU - Glaser, Stefan P.

AU - Strasser, Andreas

AU - Belz, Gabrielle T.

AU - Carotta, Sebastian

AU - Huntington, Nicholas D.

PY - 2014/8/14

Y1 - 2014/8/14

N2 - The cytokine IL-15 is required for natural killer (NK) cell homeostasis; however, the intrinsic mechanism governing this requirement remains unexplored. Here we identify the absolute requirement for myeloid cell leukaemia sequence-1 (Mcl1) in the sustained survival of NK cells in vivo. Mcl1 is highly expressed in NK cells and regulated by IL-15 in a dose-dependent manner via STAT5 phosphorylation and subsequent binding to the 3'-UTR of Mcl1. Specific deletion of Mcl1 in NK cells results in the absolute loss of NK cells from all tissues owing to a failure to antagonize pro-apoptotic proteins in the outer mitochondrial membrane. This NK lymphopenia results in mice succumbing to multiorgan melanoma metastases, being permissive to allogeneic transplantation and being resistant to toxic shock following polymicrobial sepsis challenge. These results clearly demonstrate a non-redundant pathway linking IL-15 to Mcl1 in the maintenance of NK cells and innate immune responses in vivo.

AB - The cytokine IL-15 is required for natural killer (NK) cell homeostasis; however, the intrinsic mechanism governing this requirement remains unexplored. Here we identify the absolute requirement for myeloid cell leukaemia sequence-1 (Mcl1) in the sustained survival of NK cells in vivo. Mcl1 is highly expressed in NK cells and regulated by IL-15 in a dose-dependent manner via STAT5 phosphorylation and subsequent binding to the 3'-UTR of Mcl1. Specific deletion of Mcl1 in NK cells results in the absolute loss of NK cells from all tissues owing to a failure to antagonize pro-apoptotic proteins in the outer mitochondrial membrane. This NK lymphopenia results in mice succumbing to multiorgan melanoma metastases, being permissive to allogeneic transplantation and being resistant to toxic shock following polymicrobial sepsis challenge. These results clearly demonstrate a non-redundant pathway linking IL-15 to Mcl1 in the maintenance of NK cells and innate immune responses in vivo.

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VL - 5

JO - Nature Communications

JF - Nature Communications

M1 - 4539

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Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells

Abstract

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