The histone demethylase KDM6B fine-tunes the host response to Streptococcus pneumoniae.

Graphical Abstract Highlights d NK cells acquire cell-intrinsic memory-like properties after systemic inflammation d Memory-like NK cells uncover a H3K4me1-marked enhancer at À22 kb of the ifng TSS d Memory-like NK cells persist for 9 weeks and can protect from bacterial infection d Memory-like and protective properties are methyltransferase dependent Correspondence orhan.rasid@pasteur.fr (O.R.), melanie.hamon@pasteur.fr (M.A.H.) In Brief Rasid et al. show that sepsis-like systemic inflammation induces a type of long-lasting innate immune memory in NK cells, which can protect from E. coli infection. This is achieved by revealing an enhancer of IFNg through histone monomethylation. 14 days T r a n s f e r T r a n s f e r Naïve NK cells LPS IFNG latent enhancer Memory-like NK cells H3K4me1 IFNG enhancer E.coli Protection bacteria neutrophils Naïve + Memory-like NK cells LPS H3K4me1 IFNG enhancerHigh IFNγ production Naïve + Memory-like NK cells SUMMARY Natural killer (NK) cells are unique players in innate immunity and, as such, an attractive target for immunotherapy. NK cells display immune memory properties in certain models, but the long-term status of NK cells following systemic inflammation is unknown. Here we show that following LPS-induced endotoxemia in mice, NK cells acquire cell-intrinsic memorylike properties, showing increased production of IFNg upon specific secondary stimulation. The NK cell memory response is detectable for at least 9 weeks and contributes to protection from E. coli infection upon adoptive transfer. Importantly, we reveal a mechanism essential for NK cell memory, whereby an H3K4me1-marked latent enhancer is uncovered at the ifng locus. Chemical inhibition of histone methyltransferase activity erases the enhancer and abolishes NK cell memory. Thus, NK cell memory develops after endotoxemia in a histone methylationdependent manner, ensuring a heightened response to secondary stimulation.