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

Abstract

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.