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

Differentiation and homeostasis of natural killer (NK) cells relies on common gamma-chain (?c)-dependent cytokines, in particular IL-15. Consequently, NK cells do not develop in mice with targeted ?c deletion. Herein we identify an alternative pathway of NK cell development driven by the proinflammatory cytokine IL-12, which can occur independently of ?c-signaling. In response to viral infection or upon exogenous administration, IL-12 was sufficient to elicit the emergence of a population of CD122+CD49b+ cells by specifically targeting NK cell precursors (NKPs) in the bone marrow (BM). The NK cell identity of these cells was confirmed by transcriptome-wide analyses, which further revealed a unique gene signature resembling immature NK cells. Rather than using the conventional pathway of NK cell development, IL-12-driven CD122+CD49b+ cells remained confined to a distinct stage that expresses low amounts of NK1.1 and NKp46, but differentiates into NK1.1+NKp46+ cells in the presence of ?c-cytokines. This cell population displayed anti-tumor activity and was able to limit metastatic growth. Our data reveal a novel, IL-12-driven hard-wired pathway of emergency NK lymphopoiesis bypassing steady-state ?c-signaling.