IL-15 Signaling During a Critical NK Cell Developmental Window Subverts Maturation and KIR Acquisition [CITE-seq]

However, despite the known post-conditioning spike in interleukin-15 (IL-15), NK cell maturation is frequently delayed following HSCT. We found that during in vitro NK cell development from CD34+ hematopoietic progenitor cells (HPCs), early exposure to IL-15 drove aberrant mTOR activation, resulting in epigenetic and transcriptional dysregulation and suppressed maturation and KIR acquisition.

In contrast, transiently withholding IL-15 or blocking mTOR with rapamycin produced NK cell developmental intermediates intrinsically poised to mature into highly functional, KIR-expressing NK cells. Single-cell analysis of HSCT patients at early time points post-transplant revealed a similar aberrant transcriptional signature of IL-15/mTOR overactivation in circulating donor-derived NK cells. These findings define a developmental window during which 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.