%0 Journal Article
%T Cytokines drive the formation of memory-like NK cell subsets via epigenetic rewiring and transcriptional regulation.
%A Foltz JA
%A Tran J
%A Wong P
%A Fan C
%A Schmidt E
%A Fisk B
%A Becker-Hapak M
%A Russler-Germain DA
%A Johnson J
%A Marin ND
%A Cubitt CC
%A Pence P
%A Rueve J
%A Pureti S
%A Hwang K
%A Gao F
%A Zhou AY
%A Foster M
%A Schappe T
%A Marsala L
%A Berrien-Elliott MM
%A Cashen AF
%A Bednarski JJ
%A Fertig E
%A Griffith OL
%A Griffith M
%A Wang T
%A Petti AA
%A Fehniger TA
%J Sci Immunol
%V 9
%N 96
%D 2024 Jun 28
%M 38941480
%F 30.63
%R 10.1126/sciimmunol.adk4893
%X 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.