Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells
Journal Title
Nat Commun
Publication Type
Journal Article
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.
Publisher
NPG
WEHI Research Division(s)
Molecular Immunology; Molecular Genetics Of Cancer; Immunology; Inflammation; Cancer And Haematology
Rights Notice
© 2014 Macmillan Publishers Limited. All Rights Reserved.


Creation Date: 2014-09-12 02:01:46
Last Modified: 2015-05-27 11:32:46
An error has occurred. This application may no longer respond until reloaded. Reload 🗙