EZH2 identifies the precursors of human natural killer cells with trained immunity
Objective: Trained immunity of natural killer (NK) cells has shown great potential in the treatment of cancers by eliciting enhanced effector responses to restimulation by cytokines or cancer cells for long time periods after preactivation. However, the human NK cells responsible for the generation...
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China Anti-Cancer Association
2021
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oai:doaj.org-article:1df2b004862f4f728ca74e5d394da1582021-11-30T11:27:44ZEZH2 identifies the precursors of human natural killer cells with trained immunity2095-394110.20892/j.issn.2095-3941.2020.0791https://doaj.org/article/1df2b004862f4f728ca74e5d394da1582021-11-01T00:00:00Zhttp://www.cancerbiomed.org/index.php/cocr/article/view/1980https://doaj.org/toc/2095-3941Objective: Trained immunity of natural killer (NK) cells has shown great potential in the treatment of cancers by eliciting enhanced effector responses to restimulation by cytokines or cancer cells for long time periods after preactivation. However, the human NK cells responsible for the generation and maintenance of trained immunity are largely unknown. We hypothesized that heterogeneous human NK cells would respond differentially to stimulation with a combination of IL-12, IL-15, and IL-18, and that an NK cell subset might exist that is mainly responsible for the induction of trained immunity. On the basis of our hypothesis, we aimed to identify the subset from which cytokine-trained human NK cells originate and to explore possible regulatory targets for drug intervention. Methods: Flow cytometry assays were performed to analyze the functions of cytokine-trained NK cells and examine cell division and protein expression in NK cell subsets. Single-cell RNA sequencing (scRNA-seq) plus TotalSeq™ technology was used to track the heterogeneity of NK cells during the induction of trained immunity. Results: Traditional developmental markers for peripheral NK cells were unable to identify the precursors of human NK cells with trained immunity. Therefore, we used scRNA-seq plus TotalSeq™ technology to track the heterogeneity of NK cells during the induction of trained immunity and identified a unique cluster of CD57−NKG2A+EZH2+IFNG+MKI67+IL12R+IL15R+IL18R+ NK cells. Enrichment and pseudotime trajectory analyses suggested that this cluster of NK cells contained the precursor of trained NK cells. We then used flow cytometry to further investigate the role of EZH2 in trained NK precursors and found that CD57−NKG2A+EZH2+ NK cells had faster cell cycles and an enhanced trained phenotype, and EZH2 inhibition significantly impaired the induction of trained immunity in NK cells. These results suggested that EZH2 is a unique epigenetic marker of precursors of human NK cells with trained immunity. Conclusions: Our work revealed human NK heterogeneity in the induction of trained immunity, identified the precursor subset for trained NK cells, and demonstrated the critical role of EZH2 in the induction of trained immunity in human NK cells.Chen ZhangJie YinJian ZhengJun XiaoJiajian HuYudong SuKaichen ZhouYingchi ZhangXuzhen ZhangHong ZhangQian SunYang WangWenwen YuFeng WeiQiang ZhaoLong LiXiubao RenChina Anti-Cancer Associationarticlenatural killer cellstrained immunityprecursorezh2cell cycleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancer Biology & Medicine, Vol 18, Iss 4, Pp 1021-1039 (2021) |
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natural killer cells trained immunity precursor ezh2 cell cycle Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
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natural killer cells trained immunity precursor ezh2 cell cycle Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Chen Zhang Jie Yin Jian Zheng Jun Xiao Jiajian Hu Yudong Su Kaichen Zhou Yingchi Zhang Xuzhen Zhang Hong Zhang Qian Sun Yang Wang Wenwen Yu Feng Wei Qiang Zhao Long Li Xiubao Ren EZH2 identifies the precursors of human natural killer cells with trained immunity |
| description |
Objective: Trained immunity of natural killer (NK) cells has shown great potential in the treatment of cancers by eliciting enhanced effector responses to restimulation by cytokines or cancer cells for long time periods after preactivation. However, the human NK cells responsible for the generation and maintenance of trained immunity are largely unknown. We hypothesized that heterogeneous human NK cells would respond differentially to stimulation with a combination of IL-12, IL-15, and IL-18, and that an NK cell subset might exist that is mainly responsible for the induction of trained immunity. On the basis of our hypothesis, we aimed to identify the subset from which cytokine-trained human NK cells originate and to explore possible regulatory targets for drug intervention. Methods: Flow cytometry assays were performed to analyze the functions of cytokine-trained NK cells and examine cell division and protein expression in NK cell subsets. Single-cell RNA sequencing (scRNA-seq) plus TotalSeq™ technology was used to track the heterogeneity of NK cells during the induction of trained immunity. Results: Traditional developmental markers for peripheral NK cells were unable to identify the precursors of human NK cells with trained immunity. Therefore, we used scRNA-seq plus TotalSeq™ technology to track the heterogeneity of NK cells during the induction of trained immunity and identified a unique cluster of CD57−NKG2A+EZH2+IFNG+MKI67+IL12R+IL15R+IL18R+ NK cells. Enrichment and pseudotime trajectory analyses suggested that this cluster of NK cells contained the precursor of trained NK cells. We then used flow cytometry to further investigate the role of EZH2 in trained NK precursors and found that CD57−NKG2A+EZH2+ NK cells had faster cell cycles and an enhanced trained phenotype, and EZH2 inhibition significantly impaired the induction of trained immunity in NK cells. These results suggested that EZH2 is a unique epigenetic marker of precursors of human NK cells with trained immunity. Conclusions: Our work revealed human NK heterogeneity in the induction of trained immunity, identified the precursor subset for trained NK cells, and demonstrated the critical role of EZH2 in the induction of trained immunity in human NK cells. |
| format |
article |
| author |
Chen Zhang Jie Yin Jian Zheng Jun Xiao Jiajian Hu Yudong Su Kaichen Zhou Yingchi Zhang Xuzhen Zhang Hong Zhang Qian Sun Yang Wang Wenwen Yu Feng Wei Qiang Zhao Long Li Xiubao Ren |
| author_facet |
Chen Zhang Jie Yin Jian Zheng Jun Xiao Jiajian Hu Yudong Su Kaichen Zhou Yingchi Zhang Xuzhen Zhang Hong Zhang Qian Sun Yang Wang Wenwen Yu Feng Wei Qiang Zhao Long Li Xiubao Ren |
| author_sort |
Chen Zhang |
| title |
EZH2 identifies the precursors of human natural killer cells with trained immunity |
| title_short |
EZH2 identifies the precursors of human natural killer cells with trained immunity |
| title_full |
EZH2 identifies the precursors of human natural killer cells with trained immunity |
| title_fullStr |
EZH2 identifies the precursors of human natural killer cells with trained immunity |
| title_full_unstemmed |
EZH2 identifies the precursors of human natural killer cells with trained immunity |
| title_sort |
ezh2 identifies the precursors of human natural killer cells with trained immunity |
| publisher |
China Anti-Cancer Association |
| publishDate |
2021 |
| url |
https://doaj.org/article/1df2b004862f4f728ca74e5d394da158 |
| work_keys_str_mv |
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