H3K4me1 Supports Memory-like NK Cells Induced by Systemic Inflammation

Abstract

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.

Intra-Abdominal Lipopolysaccharide Clearance and Inactivation in Peritonitis: Key Roles for Lipoproteins and the Phospholipid Transfer Protein

“…Exploring the profile of cell populations over time might have given further information about peritoneal inflammation upon LPS stimulation. For instance, it has been reported that natural killer cells that might contribute to a hyper response in sepsis by acquiring memory-like properties ( 36 ). However, ex-vivo data already exist and showed that peritoneal macrophage activation by LPS depended on both PLTP secretion by the cells and the presence of lipoproteins in the medium ( 37 ).…”

Long-term survivors of murine sepsis are predisposed to enhanced LPS-induced lung injury and proinflammatory immune reprogramming

“…NK cells have a significant role in cytokine secretion and activation of the innate immune response in acute sepsis and lung injury (89,90). Recent observations suggest NK cells are also subject to epigenetic immune reprogramming similar to trained immunity, with enhanced interferon gamma (IFN-c) secretion following remote inflammatory exposures (91,92). NK cellderived IFN-c may further propagate the enhanced cytokine and chemokine secretion observed in our model.…”

Epigenetic Regulation of NK Cell-Mediated Antitumor Immunity

“…Methylation of H3K4 is an activating mark for gene transcription. An H3K4me1-marked latent enhancer at the Ifng locus was essential for NK memory in a systemic endotoxemia model ( 87 ). The H3K4me3 demethylase Kdm5a associates with p50 and binds to the suppressor of cytokine signaling 1 (Socs1) promoter region in resting NK cells, thus leading to a repressive chromatin configuration.…”