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

Nat Commun. 2016 Dec 16:7:13708. doi: 10.1038/ncomms13708.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Gene Expression Regulation / drug effects
  • Interleukin Receptor Common gamma Subunit / genetics
  • Interleukin Receptor Common gamma Subunit / metabolism*
  • Interleukin-12 / metabolism
  • Interleukin-12 / pharmacology*
  • Killer Cells, Natural / physiology*
  • Lymphopoiesis / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Signal Transduction / immunology*
  • Vaccinia / immunology
  • Vaccinia virus

Substances

  • Cytokines
  • Interleukin Receptor Common gamma Subunit
  • Interleukin-12