학술논문
T-BET and EOMES sustain mature human NK cell identity and antitumor function
Document Type
article
Author
Pamela Wong; Jennifer A. Foltz; Lily Chang; Carly C. Neal; Tony Yao; Celia C. Cubitt; Jennifer Tran; Samantha Kersting-Schadek; Sathvik Palakurty; Natalia Jaeger; David A. Russler-Germain; Nancy D. Marin; Margery Gang; Julia A. Wagner; Alice Y. Zhou; Miriam T. Jacobs; Mark Foster; Timothy Schappe; Lynne Marsala; Ethan McClain; Patrick Pence; Michelle Becker-Hapak; Bryan Fisk; Allegra A. Petti; Obi L. Griffith; Malachi Griffith; Melissa M. Berrien-Elliott; Todd A. Fehniger
Source
The Journal of Clinical Investigation, Vol 133, Iss 13 (2023)
Subject
Language
English
ISSN
1558-8238
Abstract
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.