{"title":"DNA demethylase Tet2 promotes the terminal maturation of natural killer cells.","authors":"Yuqing Lin, Biyun Yang, Hailin Liu, Guanghe Ran, Liang Song, Meng Meng, Xiaofeng Yin, Qinghua Bi, Dongmei Yan, Youcai Deng, Yonghui Lu","doi":"10.1007/s12026-024-09506-4","DOIUrl":null,"url":null,"abstract":"<p><p>The cytotoxicity feature to eliminate malignant cells makes natural killer (NK) cells a candidate for tumor immunotherapy. However, this scenario is currently hampered by inadequate understanding of the regulatory mechanisms of NK cell development. Ten-Eleven-Translocation 2 (Tet2) is a demethylase whose mutation was recently shown to cause phenotypic defects in NK cells. However, the role of Tet2 in the development and maturation of NK cells is not entirely clear. Here we studied the modulatory role of Tet2 in NK cell development and maturation by generating hematopoietic Tet2 knockout mice and mice with Tet2 conditional deletion in NKp46<sup>+</sup> NK cells. The results showed that both hematopoietic and NK cell conditional deletion of Tet2 had no effect on the early steps of NK cell development, but impaired the terminal maturation of NK cells defined by CD11b, CD43, and KLRG1 expression. In the liver, Tet2 deletion not only prevented the terminal maturation of NK cells, but also increased the proportion of type 1 innate lymphoid cells (ILC1s) and reduced the proportion of conventional NK cells (cNK). Moreover, hematopoietic deletion of Tet2 lowered the protein levels of perforin in NK cells. Furthermore, hematopoietic deletion of Tet2 downregulated the protein levels of Eomesodermin (Eomes), but not T-bet, in NK cells. In conclusion, our results demonstrate that Tet2 plays an important role in the terminal maturation of NK cells, and the Eomes transcription factor may be involved.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":" ","pages":"908-920"},"PeriodicalIF":3.3000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Immunologic Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s12026-024-09506-4","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/6/13 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
The cytotoxicity feature to eliminate malignant cells makes natural killer (NK) cells a candidate for tumor immunotherapy. However, this scenario is currently hampered by inadequate understanding of the regulatory mechanisms of NK cell development. Ten-Eleven-Translocation 2 (Tet2) is a demethylase whose mutation was recently shown to cause phenotypic defects in NK cells. However, the role of Tet2 in the development and maturation of NK cells is not entirely clear. Here we studied the modulatory role of Tet2 in NK cell development and maturation by generating hematopoietic Tet2 knockout mice and mice with Tet2 conditional deletion in NKp46+ NK cells. The results showed that both hematopoietic and NK cell conditional deletion of Tet2 had no effect on the early steps of NK cell development, but impaired the terminal maturation of NK cells defined by CD11b, CD43, and KLRG1 expression. In the liver, Tet2 deletion not only prevented the terminal maturation of NK cells, but also increased the proportion of type 1 innate lymphoid cells (ILC1s) and reduced the proportion of conventional NK cells (cNK). Moreover, hematopoietic deletion of Tet2 lowered the protein levels of perforin in NK cells. Furthermore, hematopoietic deletion of Tet2 downregulated the protein levels of Eomesodermin (Eomes), but not T-bet, in NK cells. In conclusion, our results demonstrate that Tet2 plays an important role in the terminal maturation of NK cells, and the Eomes transcription factor may be involved.
消除恶性细胞的细胞毒性特征使自然杀伤(NK)细胞成为肿瘤免疫疗法的候选细胞。然而,由于对 NK 细胞发育的调控机制了解不足,这一设想目前受到阻碍。十-十一-转移定位 2(Tet2)是一种去甲基化酶,最近的研究表明其突变会导致 NK 细胞的表型缺陷。然而,Tet2 在 NK 细胞发育和成熟过程中的作用尚不完全清楚。在这里,我们通过产生造血Tet2基因敲除小鼠和NKp46+ NK细胞中Tet2条件性缺失小鼠,研究了Tet2在NK细胞发育和成熟中的调节作用。结果表明,造血和NK细胞条件性缺失Tet2对NK细胞发育的早期步骤没有影响,但会损害以CD11b、CD43和KLRG1表达为标准的NK细胞的终末成熟。在肝脏中,Tet2 基因缺失不仅阻止了 NK 细胞的终末成熟,还增加了 1 型先天性淋巴细胞(ILC1s)的比例,降低了传统 NK 细胞(cNK)的比例。此外,Tet2的造血缺失降低了NK细胞中穿孔素的蛋白水平。此外,Tet2的造血缺失会降低NK细胞中Eomesodermin(Eomes)的蛋白水平,但不会降低T-bet的蛋白水平。总之,我们的研究结果表明,Tet2 在 NK 细胞的终末成熟过程中发挥着重要作用,Eomes 转录因子可能也参与其中。
期刊介绍:
IMMUNOLOGIC RESEARCH represents a unique medium for the presentation, interpretation, and clarification of complex scientific data. Information is presented in the form of interpretive synthesis reviews, original research articles, symposia, editorials, and theoretical essays. The scope of coverage extends to cellular immunology, immunogenetics, molecular and structural immunology, immunoregulation and autoimmunity, immunopathology, tumor immunology, host defense and microbial immunity, including viral immunology, immunohematology, mucosal immunity, complement, transplantation immunology, clinical immunology, neuroimmunology, immunoendocrinology, immunotoxicology, translational immunology, and history of immunology.