T-BET and EOMES sustain mature human NK cell identity and antitumor function.
T-BET and EOMES sustain mature human NK cell identity and antitumor function.
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DOI：
10.1172/jci162530
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发表时间：
2023-07-03
影响因子：
15.9
通讯作者：
Fehniger, Todd A.
中科院分区：
文献类型：
--
作者：
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.
由于T-box转录因子（TF）T-BET和EOMES是NK细胞发育启动所必需的，因此它们对成熟NK细胞稳态、功能和分子编程的持续需求仍不清楚。为了解决这个问题，使用CRISPR/Cas9在未扩增的原代人NK细胞中删除T-BET和EOMES。删除这些TF会损害人NK细胞的体内抗肿瘤应答。从机制上讲，T-BET和EOMES是体内正常NK细胞增殖和持久性所必需的。缺乏T-BET和EOMES的NK细胞也表现出对细胞因子刺激的缺陷反应。单细胞RNA-Seq揭示了人NK细胞中的特异性T-box转录程序，该程序在T-BET和EOMES缺失后迅速丢失。此外，T-BET-和EOMES-缺失的CD 56 bright NK细胞获得了先天性淋巴细胞趋化因子样（ILCP样）特征，其中ILC-3相关TF RORC和AHR的表达增加，揭示了T-box TF在维持成熟NK细胞表型中的作用和抑制替代ILC谱系的意想不到的作用。我们的研究揭示了持续的EOMES和T-BET表达对协调成熟NK细胞功能和身份的至关重要性。
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.