Abstract
Abstract Killer immunoglobulin-like receptors (KIRs) allow natural killer (NK) cells to recognize and kill tumor cells. The mechanisms that control KIR acquisition during human NK cell development are not known. We previously observed that while human tonsil innate lymphoid cell precursors (ILCPs) could become KIR+ NK cells in immune deficient mice treated with interleukin (IL)-15, ILCPs cultured in vitro with IL-15 and OP9-DL1 stroma generated only rare KIR+ NK cells, suggesting that additional signals are required in vitro. To test this hypothesis, we cultured ILCPs with OP9-DL1 stroma and +/- allogeneic blood CD34+ hematopoietic progenitor cells (HPCs), which on their own can become KIR+ NK cells when cultured as follows: two weeks in Flt3 ligand (FL), c-Kit ligand (KL), and IL-3 followed by two weeks in FL, KL, and IL-15. Remarkably, among the ILCP-derived NK cells, significantly more were KIR+ when derived with HPCs (14.5+/-2.9% w/HPCs vs 1.9+/-0.8% w/out HPCs, p=0.004, n=7). Interestingly, we also observed that when IL-15 was added at day (d)0 instead of at d14, significantly fewer KIR+ NK cells were produced (IL-15 at d0: 3.3+/-0.7% vs IL-15 at d14: 14.5+/-2.9%, p=0.001, n=7). Lastly, we noted epigenetic and transcriptional alterations with IL-15 added at d0 vs d14. Collectively, these data suggest that ILCP differentiation into KIR+ NK cells requires epigenetic priming in a conducive microenvironment and that early exposure to exogenous IL-15 subverts this process.
Published Version
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