Interleukin-12 bypasses common gamma-chain signalling in emergency natural killer cell lymphopoiesis

Isabel Ohs, Maries van den Broek, Kathrin Nussbaum, Christian Münz, Sebastian J. Arnold, Sergio A. Quezada, Sonia Tugues and Burkhard Becher ()
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Isabel Ohs: Inflammation Research, Institute of Experimental Immunology, University of Zurich
Maries van den Broek: Tumor Immunology, Institute of Experimental Immunology, University of Zurich
Kathrin Nussbaum: Inflammation Research, Institute of Experimental Immunology, University of Zurich
Christian Münz: Viral Immunobiology, Institute of Experimental Immunology, University of Zurich
Sebastian J. Arnold: Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, and BIOSS Centre of Biological Signalling Studies, Albert-Ludwigs-University
Sergio A. Quezada: Cancer Immunology Unit, University College London Cancer Institute
Sonia Tugues: Inflammation Research, Institute of Experimental Immunology, University of Zurich
Burkhard Becher: Inflammation Research, Institute of Experimental Immunology, University of Zurich

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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 NK1.1lowNKp46low stage, 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.

Date: 2016
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DOI: 10.1038/ncomms13708

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