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.
authors.affiliation: 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].
authors.forename: Priyanka
authors.initials: P
authors.lastname: Sathe
authors.affiliation: 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].
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Delconte
authors.affiliation: 1] QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia [2] School of Medicine, University of Queensland, Herston, Queensland 4006, Australia.
authors.forename: Fernando
authors.initials: F
authors.lastname: Souza-Fonseca-Guimaraes
authors.affiliation: 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.
authors.forename: Cyril
authors.initials: C
authors.lastname: Seillet
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Chopin
authors.affiliation: 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.
authors.forename: Cassandra J
authors.initials: CJ
authors.lastname: Vandenberg
authors.affiliation: 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.
authors.forename: Lucille C
authors.initials: LC
authors.lastname: Rankin
authors.affiliation: 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.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Mielke
authors.affiliation: 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.
authors.forename: Ingela
authors.initials: I
authors.lastname: Vikstrom
authors.affiliation: 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.
authors.forename: Tatiana B
authors.initials: TB
authors.lastname: Kolesnik
authors.affiliation: 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.
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Nicholson
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, INSERM, Marseille U1104, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Vivier
authors.affiliation: 1] QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia [2] School of Medicine, University of Queensland, Herston, Queensland 4006, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.affiliation: 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.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nutt
authors.affiliation: 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.
authors.forename: Stefan P
authors.initials: SP
authors.lastname: Glaser
authors.affiliation: 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.
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.affiliation: 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.
authors.forename: Gabrielle T
authors.initials: GT
authors.lastname: Belz
authors.affiliation: 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.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Carotta
authors.affiliation: 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.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Huntington
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D017353:Gene Deletion; D007154:Immune System Diseases / Q000235:genetics* / Q000503:physiopathology; D007113:Immunity, Innate / Q000235:genetics* / Q000502:physiology; D019409:Interleukin-15 / Q000494:pharmacology / Q000502:physiology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008231:Lymphopenia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics* / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016207:Cytokines; D019409:Interleukin-15; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D050799:STAT5 Transcription Factor