TY - JOUR
T1 - T-BET and EOMES sustain mature human NK cell identity and antitumor function
AU - Wong, Pamela
AU - Foltz, Jennifer A.
AU - Chang, Lily
AU - Neal, Carly C.
AU - Yao, Tony
AU - Cubitt, Celia C.
AU - Tran, Jennifer
AU - Kersting-Schadek, Samantha
AU - Palakurty, Sathvik
AU - Jaeger, Natalia
AU - Russler-Germain, David A.
AU - Marin, Nancy D.
AU - Gang, Margery
AU - Wagner, Julia A.
AU - Zhou, Alice Y.
AU - Jacobs, Miriam T.
AU - Foster, Mark
AU - Schappe, Timothy
AU - Marsala, Lynne
AU - McClain, Ethan
AU - Pence, Patrick
AU - Becker-Hapak, Michelle
AU - Fisk, Bryan
AU - Petti, Allegra A.
AU - Griffith, Obi L.
AU - Griffith, Malachi
AU - Berrien-Elliott, Melissa M.
AU - Fehniger, Todd A.
N1 - Publisher Copyright:
Copyright: © 2023, Wong et al.
PY - 2023/7/3
Y1 - 2023/7/3
N2 - Since the T-box transcription factors (TFs) T-BET and EOMES are necessary for initiation of NK cell development, their ongoing requirement for mature NK cell homeostasis, function, and molecular programming remains unclear. To address this, T-BET and EOMES were deleted in unexpanded primary human NK cells using CRISPR/Cas9. Deleting these TFs compromised in vivo antitumor response of human NK cells. Mechanistically, T-BET and EOMES were required for normal NK cell proliferation and persistence in vivo. NK cells lacking T-BET and EOMES also exhibited defective responses to cytokine stimulation. Single-cell RNA-Seq revealed a specific T-box transcriptional program in human NK cells, which was rapidly lost following T-BET and EOMES deletion. Further, T-BET– and EOMES-deleted CD56bright NK cells acquired an innate lymphoid cell precursor–like (ILCP-like) profile with increased expression of the ILC-3–associated TFs RORC and AHR, revealing a role for T-box TFs in maintaining mature NK cell phenotypes and an unexpected role of suppressing alternative ILC lineages. Our study reveals the critical importance of sustained EOMES and T-BET expression to orchestrate mature NK cell function and identity.
AB - Since the T-box transcription factors (TFs) T-BET and EOMES are necessary for initiation of NK cell development, their ongoing requirement for mature NK cell homeostasis, function, and molecular programming remains unclear. To address this, T-BET and EOMES were deleted in unexpanded primary human NK cells using CRISPR/Cas9. Deleting these TFs compromised in vivo antitumor response of human NK cells. Mechanistically, T-BET and EOMES were required for normal NK cell proliferation and persistence in vivo. NK cells lacking T-BET and EOMES also exhibited defective responses to cytokine stimulation. Single-cell RNA-Seq revealed a specific T-box transcriptional program in human NK cells, which was rapidly lost following T-BET and EOMES deletion. Further, T-BET– and EOMES-deleted CD56bright NK cells acquired an innate lymphoid cell precursor–like (ILCP-like) profile with increased expression of the ILC-3–associated TFs RORC and AHR, revealing a role for T-box TFs in maintaining mature NK cell phenotypes and an unexpected role of suppressing alternative ILC lineages. Our study reveals the critical importance of sustained EOMES and T-BET expression to orchestrate mature NK cell function and identity.
UR - http://www.scopus.com/inward/record.url?scp=85164211360&partnerID=8YFLogxK
U2 - 10.1172/JCI162530
DO - 10.1172/JCI162530
M3 - Article
C2 - 37279078
AN - SCOPUS:85164211360
SN - 0021-9738
VL - 133
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 13
M1 - e162530
ER -