NK cells acquire epigenetic memory of LPS-induced systemic inflammation

Natural killer cells are unique mediators of innate immunity, and as such, an attractive target for immunotherapy. Following viral infection, NK cells display immune memory properties, defined by heightened responses to re-stimulation, an expansion of specific NK cell sup-populations and a protective role against re-infection. However, similar memory to bacterial infection or systemic inflammation, and the molecular mechanisms behind NK cell memory remain elusive. Here we show that following LPS-induced endotoxemia in mice, NK cells acquire cell-intrinsic memory properties as displayed by an amplified production of IFN{gamma} upon secondary stimulation. NK cell memory is acquired even under the post-endotoxemic suppressive environment and is detectable for at least 9 weeks. Furthermore, we define an epigenetic mechanism essential for NK cell memory, where an H3K4me1-marked latent enhancer is uncovered at the ifng locus. Chemical inhibition of histone methyltransferase activity erased the enhancer and prevented NK cells from acquiring memory. Thus, NK cells develop memory to LPS during endotoxemia, in a histone methylation-dependent manner, which ensures a heightened response to secondary stimulation and confers protection against bacterial infection.