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PMID: 25119382 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells.

Nature communications ·Vol. 5 ·2014-08-14 ·Pages 4539

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

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.

MeSH Terms
Animals Apoptosis/drug effects,physiology Cytokines/pharmacology Disease Models, Animal Dose-Response Relationship, Drug Female Gene Deletion Immune System Diseases/genetics,physiopathology Immunity, Innate/genetics,physiology Interleukin-15/pharmacology,physiology Killer Cells, Natural/drug effects,metabolism,pathology Lymphopenia/genetics,pathology,physiopathology Male Mice Mice, Inbred C57BL Myeloid Cell Leukemia Sequence 1 Protein/genetics,metabolism STAT5 Transcription Factor/physiology Signal Transduction/physiology
Chemicals
Cytokines Interleukin-15 Mcl1 protein, mouse Myeloid Cell Leukemia Sequence 1 Protein STAT5 Transcription Factor
Authors & Affiliations
19 authors, click to expand affiliations / ORCID
Sathe Priyanka
1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Victoria 3010, Australia [3].
Delconte Rebecca B
1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Victoria 3010, Australia [3].
Souza-Fonseca-Guimaraes Fernando
1] QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia [2] School of Medicine, University of Queensland, Herston, Queensland 4006, Australia.
Seillet Cyril
1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
Chopin Michael
1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
Vandenberg Cassandra J
1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
Rankin Lucille C
1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
Mielke Lisa A
1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
Vikstrom Ingela
1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
Kolesnik Tatiana B
1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
Nicholson Sandra E
1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
Vivier Eric
Centre d'Immunologie de Marseille-Luminy, INSERM, Marseille U1104, France.
Smyth Mark J
1] QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia [2] School of Medicine, University of Queensland, Herston, Queensland 4006, Australia.
Nutt Stephen L
1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
Glaser Stefan P
1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
Strasser Andreas
1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
Belz Gabrielle T
1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
Carotta Sebastian
1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
Huntington Nicholas D
1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
Published
2014-08-14
Epub
2014-00-14
Pages
4539
Language
English
Region
England
NLM ID
101528555
Subset
IM
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