IL-15 signaling during a critical NK cell developmental window subverts maturation and KIR acquisition.

Natural killer (NK) cells are key mediators of immune surveillance following hematopoietic stem cell transplantation (HSCT). However, despite the post-conditioning spike in interleukin-15 (IL-15), NK cell maturation is frequently delayed following HSCT. Here, we show that during in vitro NK cell development from CD34+ hematopoietic progenitor cells, early exposure to IL-15 drives aberrant mTOR activation, resulting in DNA methylation and transcriptional dysregulation with suppressed maturation and KIR acquisition. In contrast, transiently withholding IL-15 or inhibition of mTOR with rapamycin generates NK cell developmental intermediates intrinsically poised to mature into highly functional, KIR-expressing NK cells. Single-cell analysis of HSCT patients at early post-transplant time points reveals a similar aberrant transcriptional signature of IL-15/mTOR overactivation in circulating donor-derived NK cells. These findings identify a developmental window when IL-15 signaling can paradoxically subvert NK cell maturation and KIR acquisition, suggesting that temporally regulated cytokine signaling could accelerate immune reconstitution and improve therapeutic efficacy.