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 languageEnglish
Article number4539
Number of pages10
JournalNature Communications
Volume5
DOIs
Publication statusPublished - 14 Aug 2014
Externally publishedYes

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