The Transcription Factor Tcf1 Contributes to Normal NK Cell Development and Function by Limiting the Expression of Granzymes
The Transcription Factor Tcf1 Contributes to Normal NK Cell Development and Function by Limiting the Expression of Granzymes
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DOI：
10.1016/j.celrep.2017.06.071
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发表时间：
2017-07-18
期刊：
影响因子：
8.8
通讯作者：
Held, Werner
中科院分区：
文献类型：
--
作者：
Jeevan-Raj, Beena;Gehrig, Jasmine;Held, Werner
转录因子Tcf1是自然杀伤(NK)细胞发育所必需的。然而，它的确切作用还没有得到澄清。我们对Tcf1缺陷小鼠和转基因小鼠的联合分析表明，Tcf1引导NK细胞经历了三个发育阶段。Tcf1的表达将引导骨髓祖细胞向NK细胞方向发展，并保证NK细胞的存活，而Tcf1的表达下调是最终成熟所必需的。NK细胞的存活受损是由于颗粒酶B(GzmB)和其他颗粒酶家族成员的过度表达，导致NK细胞在成熟过程中以及在被细胞因子或靶细胞激活后自毁。从机制上讲，Tcf1结合降低了Gzmb相关调节元件的活性，这是表达Tcf1的NK细胞中Gzmb表达减少的原因。这些数据表明，为了NK细胞的正常扩张和功能，需要限制细胞毒效应分子的表达，这是意想不到的要求。
The transcription factor Tcf1 is essential for the development of natural killer (NK) cells. However, its precise role has not been clarified. Our combined analysis of Tcf1-deficient and transgenic mice indicated that Tcf1 guides NK cells through three stages of development. Tcf1 expression directed bone marrow progenitors toward the NK cell lineage and ensured the survival of NK-committed cells, and its downregulation was needed for terminal maturation. Impaired survival of NK-committed cells was due to excessive expression of granzyme B (GzmB) and other granzyme family members, which induced NK cell self-destruction during maturation and following activation with cytokines or target cells. Mechanistically, Tcf1 binding reduced the activity of a Gzmb-associated regulatory element, and this accounted for the reduced Gzmb expression in Tcf1-expressing NK cells. These data identify an unexpected requirement to limit the expression of cytotoxic effector molecules for the normal expansion and function of NK cells.