title: Interleukin-12 bypasses common gamma-chain signalling in emergency natural killer cell lymphopoiesis.
abstract: Differentiation and homeostasis of natural killer (NK) cells relies on common gamma-chain (γc)-dependent cytokines, in particular IL-15. Consequently, NK cells do not develop in mice with targeted γc deletion. Herein we identify an alternative pathway of NK-cell development driven by the proinflammatory cytokine IL-12, which can occur independently of γc-signalling. In response to viral infection or upon exogenous administration, IL-12 is sufficient to elicit the emergence of a population of CD122+CD49b+cells by targeting NK-cell precursors (NKPs) in the bone marrow (BM). We confirm the NK-cell identity of these cells by transcriptome-wide analyses and their ability to eliminate tumour cells. Rather than using the conventional pathway of NK-cell development, IL-12-driven CD122+CD49b+cells remain confined to a NK1.1lowNKp46lowstage, but differentiate into NK1.1+NKp46+cells in the presence of γc-cytokines. Our data reveal an IL-12-driven hard-wired pathway of emergency NK-cell lymphopoiesis bypassing steady-state γc-signalling.
authors.affiliation: Inflammation Research, Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Isabel
authors.initials: I
authors.lastname: Ohs
authors.affiliation: Tumor Immunology, Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Maries
authors.initials: M
authors.lastname: van den Broek
authors.affiliation: Inflammation Research, Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Nussbaum
authors.affiliation: Viral Immunobiology, Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Münz
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, and BIOSS Centre of Biological Signalling Studies, Albert-Ludwigs-University, D-79104 Freiburg, Germany.|BIOSS Centre of Biological Signalling Studies, Albert-Ludwigs-University, D-79104 Freiburg, Germany.
authors.forename: Sebastian J
authors.initials: SJ
authors.lastname: Arnold
authors.affiliation: Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, WC1E 6BT London, UK.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Quezada
authors.affiliation: Inflammation Research, Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Sonia
authors.initials: S
authors.lastname: Tugues
authors.affiliation: Inflammation Research, Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Burkhard
authors.identifier: 0000-0002-1541-7867
authors.initials: B
authors.lastname: Becher
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000502:physiology*; D038041:Lymphopoiesis / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology*; D014615:Vaccinia / Q000276:immunology; D014616:Vaccinia virus
chemical_list: D016207:Cytokines; D053631:Interleukin Receptor Common gamma Subunit; D018664:Interleukin-12