Stage-Specific Requirement for Eomes in Mature NK Cell Homeostasis and Cytotoxicity
Stage-Specific Requirement for Eomes in Mature NK Cell Homeostasis and Cytotoxicity
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DOI：
10.1016/j.celrep.2020.107720
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发表时间：
2020-06-02
期刊：
影响因子：
8.8
通讯作者：
Fehniger, Todd A.
中科院分区：
文献类型：
--
作者：
Wagner, Julia A.;Wong, Pamela;Fehniger, Todd A.
自然杀伤（NK）细胞是介导抗病毒和抗肿瘤反应的细胞毒性先天淋巴样细胞（ILC），并且需要转录调节因子Eomesodermin（Eomes）用于早期发育。然而，Eomes及其分子程序在成熟NK细胞生物学中的作用尚不清楚。为了解决这个问题，我们开发了他莫昔芬诱导的I型ILC特异性（Ncr 1靶向的）cre小鼠，并将其与Eomes-floxed小鼠结合联合收割机。正常NK细胞个体发生后Eomes缺失导致NK细胞（但不是ILC 1）的快速损失，对倒数第二成熟的III期NK细胞具有特别深远的影响。负责阶段III减少的机制包括增加的凋亡和受损的成熟从阶段II前体。诱导的Eomes缺失也降低NK细胞的细胞毒性，并消除体内排斥的主要组织相容性复合体（MHC）-I类缺陷细胞。然而，其他NK细胞功能反应和IV期NK细胞在很大程度上被保留。这些数据表明，成熟的NK细胞具有不同的Eomes依赖性和非依赖性阶段。
Natural killer (NK) cells are cytotoxic innate lymphoid cells (ILCs) that mediate antiviral and antitumor responses and require the transcriptional regulator Eomesodermin (Eomes) for early development, However, the role of Eomes and its molecular program in mature NK cell biology is unclear To address this, we develop a tamoxifen-inducible, type-I -ILC-specific (Ncr1-targeted) cre mouse and combine this with Eomes-floxed mice. Eomes deletion after normal NK cell ontogeny results in a rapid loss of NK cells (but not ILC1s), with a particularly profound effect on penultimately mature stage III NK cells. Mechanisms responsible for stage III reduction include increased apoptosis and impaired maturation from stage II precursors. Induced Eomes deletion also decreases NK cell cytotoxicity and abrogates in vivo rejection of major histocompatibility complex (MHC)-class-I-deficient cells. However, other NK cell functional responses, and stage IV NK cells, are largely preserved. These data indicate that mature NK cells have distinct Eomes-dependent and -independent stages.