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Natural killer (NK) cell memory can be established in response to short-term stimulation with myeloid-derived cytokines, specifically, IL-12, IL-15, and IL-18. Memory NK cells have been shown to produce more interferon-gamma and display higher cytotoxic function upon re-challenge, compared to unstimulated NK cells, much like adaptive cytotoxic T-cells. Memory NK cells have been demonstrated to display increased killing of leukemic tumor cells and are currently in clinical trials for cancer cellular therapy. Other recent studies have also identified that memory NK cells expand in response to infections, such as tuberculosis and HIV-1. However, it remains unclear the precise transcriptional programs that govern the transition of NK cells to memory NK cells and how this this long-term cellular phenotype is preserved. Here, we utilized single-cell RNA-sequencing (scRNA-seq) to study the dynamics of the transcriptome of NK cells during memory establishment. We stimulated human peripheral blood NK cells from five distinct donors overnight with the myeloid cytokine cocktail, or a basal amount of IL-15 as a control, and performed scRNA-seq at two, three- and eight-days post-stimulation. We observed alterations in metabolic genomic signatures, including an upregulation of reduction-oxidation transcripts associated with oxidative stress mitigation in the primed samples at days two and eight, indicating key changes in metabolic pathways. Defining the NK cell transcriptome during memory establishment will reveal potential targets for exploitation during vaccine design against pathogens such as HIV-1, or to overcome barriers related to immunotherapy. Our findings define novel transcriptional trajectories for memory NK cell differentiation up to one week post exposure and suggest that resting memory NK cells readily express metabolic machinery associated with enhanced cytotoxic function and cytokine secretion.

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Decoding The Transcriptional Programs Governing Natural Killer Cell Memory Establishment