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Wong, Pamela; Foltz, Jennifer A; Chang, Lily; Neal, Carly C; Yao, Tony; Cubitt, Celia C; Tran, Jennifer; Kersting-Schadek, Samantha; Palakurty, Sathvik; Jaeger, Natalia; Russler-Germain, David A; Marin, Nancy D; Gang, Margery; Wagner, Julia A; Zhou, Alice Y; Jacobs, Miriam T; Foster, Mark; Schappe, Timothy; Marsala, Lynne; McClain, Ethan; Pence, Patrick; Becker-Hapak, Michelle; Fisk, Bryan; Petti, Allegra A; Griffith, Obi L; Griffith, Malachi; Berrien-Elliott, Melissa M; Fehniger, Todd A
The Journal of clinical investigation, 07/2023, Letnik: 133, Številka: 13Journal Article
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.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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