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

Early IL-15 exposure during in vitro NK cell development from CD34+ progenitors drives aberrant mTOR activation, suppressing maturation and KIR acquisition via DNA methylation and transcriptional dysregulation.

• Why it matters: After HSCT, IL-15 levels spike yet NK maturation is often delayed, and the mechanisms linking IL-15 signaling timing to impaired maturation and KIR acquisition are unclear.
• What they did: The study used in vitro NK development with early IL-15 exposure, compared with transient IL-15 withholding or rapamycin mTOR inhibition, plus single-cell analysis of early post-transplant patient samples.
• The result: Withholding IL-15 or inhibiting mTOR generates intermediates poised to mature into highly functional, KIR-expressing NK cells, and patient data show a similar IL-15/mTOR overactivation transcriptional signature.

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