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

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.

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Publication Details

Journal
Cell Reports
Published
2026-09-16
DOI
https://doi.org/10.1016/j.celrep.2026.117999
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
0.00

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

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

Bethany L. Mundy-Bosse, Megan Broughton, Christopher C. Oakes, Aharon G. Freud, Caprice D. Eisele, Ella Troy, Ansel P. Nalin, Amir Horowitz, Stephen K. Anderson, Kinda Sara, Isaac Elmer, Roshini S. Abraham, Noah T. Koenigs, Kyoko Yamaguchi, Michael A. Ruesch
article en

Abstract

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.

Cell ReportsVol. 45(10)
Brigham Young University (US), Nationwide Children's Hospital (US), The University of Texas MD Anderson Cancer Center (US), Virginia Commonwealth University (US), Frederick National Laboratory for Cancer Research (US), The Ohio State University (US), Icahn School of Medicine at Mount Sinai (US)
American Cancer Society, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Frederick National Laboratory for Cancer Research, National Cancer Institute
Zero hunger
Openalex Percentile: Top 18%
Immune Cell Function and Interaction
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