title: NK Cell-Specific Gata3 Ablation Identifies the Maturation Program Required for Bone Marrow Exit and Control of Proliferation.
abstract: NK cells are innate lymphocytes capable of eliciting an innate immune response to pathogens. NK cells develop and become mature in the bone marrow (BM) before they migrate out to peripheral organs. Although the developmental program leading to mature NK cells has been studied in the context of several transcription factors, the stage-specific role of GATA3 in NK cell development has been incompletely understood. Using NKp46-Cre-Gata3(fl/fl) mice in which Gata3 deficiency was induced as early as the immature stage of NK cell differentiation, we demonstrated that GATA3 is required for the NK cell maturation beyond the CD27 single-positive stage and is indispensable for the maintenance of liver-resident NK cells. The frequencies of NK cells from NKp46-Cre-Gata3(fl/fl) mice were found higher in the BM but lower in peripheral organs compared with control littermates, indicating that GATA3 controls the maturation program required for BM egress. Despite the defect in maturation, upon murine CMV infection, NK cells from NKp46-Cre-Gata3(fl/fl) mice expanded vigorously, achieving NK cell frequencies surpassing those in controls and therefore provided comparable protection. The heightened proliferation of NK cells from NKp46-Cre-Gata3(fl/fl) mice was cell intrinsic and associated with enhanced upregulation of CD25 expression. Taken together, our results demonstrate that GATA3 is a critical regulator for NK cell terminal maturation and egress out of the BM and that immature NK cells present in the periphery of NKp46-Cre-Gata3(fl/fl) mice can rapidly expand and provide a reservoir of NK cells capable of mounting an efficient cytotoxic response upon virus infection.
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada;
authors.forename: Alaa Kassim
authors.initials: AK
authors.lastname: Ali
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada;
authors.forename: Jun Seok
authors.initials: JS
authors.lastname: Oh
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université UM2, INSERM, U1104, CNRS UMR7280, 13288 Marseille, France; Immunologie, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, 13385 Marseille, France; and.
authors.forename: Eric
authors.initials: E
authors.lastname: Vivier
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, Vienna 1030, Austria.
authors.forename: Meinrad
authors.initials: M
authors.lastname: Busslinger
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada; seunglee@uottawa.ca.
authors.forename: Seung-Hwan
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation; D005434:Flow Cytometry; D050485:GABA Plasma Membrane Transport Proteins / Q000276:immunology*; D055786:Gene Knockout Techniques; D007113:Immunity, Innate / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology* / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D038041:Lymphopoiesis / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; C493419:Slc6a13 protein, mouse