title: The Helix-Loop-Helix Protein ID2 Governs NK Cell Fate by Tuning Their Sensitivity to Interleukin-15.
abstract: The inhibitor of DNA binding 2 (Id2) is essential for natural killer (NK) cell development with its canonical role being to antagonize E-protein function and alternate lineage fate. Here we have identified a key role for Id2 in regulating interleukin-15 (IL-15) receptor signaling and homeostasis of NK cells by repressing multiple E-protein target genes including Socs3. Id2 deletion in mature NK cells was incompatible with their homeostasis due to impaired IL-15 receptor signaling and metabolic function and this could be rescued by strong IL-15 receptor stimulation or genetic ablation of Socs3. During NK cell maturation, we observed an inverse correlation between E-protein target genes and Id2. These results shift the current paradigm on the role of ID2, indicating that it is required not only to antagonize E-proteins during NK cell commitment, but constantly required to titrate E-protein activity to regulate NK cell fitness and responsiveness to IL-15.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, VIC 3010 Australia.
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Delconte
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, VIC 3010 Australia; Department of Computing and Information Systems, The University of Melbourne, VIC 3010, Australia.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, VIC 3010 Australia.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Sathe
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, VIC 3010 Australia.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ushiki
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, VIC 3010 Australia.
authors.forename: Cyril
authors.initials: C
authors.lastname: Seillet
authors.affiliation: Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, 1030 Vienna, Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Minnich
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, VIC 3010 Australia.
authors.forename: Tatiana B
authors.initials: TB
authors.lastname: Kolesnik
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, VIC 3010 Australia.
authors.forename: Lucille C
authors.initials: LC
authors.lastname: Rankin
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, VIC 3010 Australia.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Mielke
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, VIC 3010 Australia.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Zhang
authors.affiliation: Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, 1030 Vienna, Austria.
authors.forename: Meinrad
authors.initials: M
authors.lastname: Busslinger
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; School of Medicine, University of Queensland, Herston, QLD 4006, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmacological Science, Parkville, VIC 3052, Australia.
authors.forename: Dana S
authors.initials: DS
authors.lastname: Hutchinson
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, VIC 3010 Australia.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nutt
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, VIC 3010 Australia.
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Nicholson
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, VIC 3010 Australia.
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, VIC 3010 Australia.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Corcoran
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université UM2, Inserm, U1104, CNRS UMR7280, 13288 Marseille, France; Immunologie, Hôpital de la Comception, Assistance Publique des Hôpitaux de Marseille, 13385 Marseille, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Vivier
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia. Electronic address: belz@wehi.edu.au.
authors.forename: Gabrielle T
authors.initials: GT
authors.lastname: Belz
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Carotta
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia. Electronic address: huntington@wehi.edu.au.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Huntington
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D019070:Cell Lineage / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D051797:Inhibitor of Differentiation Protein 2 / Q000276:immunology*; D019409:Interleukin-15 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000166:cytology* / Q000276:immunology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D053647:Receptors, Interleukin-15 / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism
chemical_list: C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D019409:Interleukin-15; D053647:Receptors, Interleukin-15; D014157:Transcription Factors