Immune Cell Function and Interaction
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It is discovered that NK cell activation with IL-12/15/18 results in previously unappreciated diverse cellular fates and identifies new strategies to enhance NK therapies, shed light on the molecular mechanisms governing cytokine-induced NK memory and may help to inform NK-based immunotherapies.
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Activation of natural killer (NK) cells with the cytokines interleukin-12 (IL-12), IL-15, and IL-18 induces their differentiation into memory-like (ML) NK cells; however, the underlying epigenetic and transcriptional mechanisms are unclear. By combining ATAC-seq, CITE-seq, and functional analyses, we discovered that IL-12/15/18 activation results in two main human NK fates: reprogramming into enriched memory-like (eML) NK cells or priming into effector conventional NK (effcNK) cells. eML NK cells had distinct transcriptional and epigenetic profiles and enhanced function, whereas effcNK cells resembled cytokine-primed cNK cells. Two transcriptionally discrete subsets of eML NK cells were also identified, eML-1 and eML-2, primarily arising from CD56bright or CD56dim mature NK cell subsets, respectively. Furthermore, these eML subsets were evident weeks after transfer of IL-12/15/18-activated NK cells into patients with cancer. Our findings demonstrate that NK cell activation with IL-12/15/18 results in previously unappreciated diverse cellular fates and identifies new strategies to enhance NK therapies.
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@article{Foltz2024Cytokines,
title = {Cytokines drive the formation of memory-like NK cell subsets via epigenetic rewiring and transcriptional regulation},
author = {Jennifer A. Foltz and Jennifer Tran and Pamela Wong and Changxu Fan and E. E. Schmidt and Bryan Fisk and Michelle Becker‐Hapak and David A. Russler‐Germain and Jeanette Johnson and Nancy D. Marin and Celia C. Cubitt and Patrick Pence and Joseph Rueve and Sushanth Pureti and Kimberly Hwang and Feng Gao and Alice Y. Zhou and Mark P. Foster and Timothy Schappe and Lynne Marsala and Melissa M. Berrien-Elliott and Amanda F. Cashen and Jeffrey J. Bednarski and Elana J. Fertig and Obi L. Griffith and Malachi Griffith and Ting Wang and Allegra A. Petti and Todd A. Fehniger},
journal = {Science Immunology},
year = {2024},
doi = {10.1126/sciimmunol.adk4893},
url = {https://doi.org/10.1126/sciimmunol.adk4893}
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