Hypoxia-inducible factor 2-alpha promotes fitness of cytokine-activated human natural killer cells

IL-2 or IL-15 increases HIF-2 (EPAS1) protein in human NK cells, and blocking HIF-2 markedly compromises survival of cytokine-activated NK cells.

• Why it matters: Durable antiviral and antitumor activity depends on NK cell fitness and persistence, but the cytokine-driven transcriptional programs that sustain viability are not well defined.
• What they did: Human NK cells from healthy blood donors were cultured with IL-2 or IL-15, then EPAS1 was disrupted by CRISPR or HIF-2 was inhibited pharmacologically; HIF-2/HIF-1{beta} heterodimer formation was also blocked.
• The result: HIF-2 induction was not linked to limited oxygen, and HIF-2 inhibition reduced NK cell survival, while blocking canonical HIF-2 transcriptional activity showed no apparent effects on viability, function, or metabolism.

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