近日,，來(lái)自美國(guó)芝加哥大學(xué)的研究人員表示，轉(zhuǎn)錄因子ETS1對(duì)自然殺傷(NK)細(xì)胞具有重要的調(diào)節(jié)作用,。而缺乏ETS1的NK細(xì)胞，會(huì)出現(xiàn)基因失調(diào)及慢性免疫激活,。相關(guān)研究成果于5月17日在線發(fā)表在Immunity上,。
轉(zhuǎn)錄因子是能夠結(jié)合在基因上游特異核苷酸序列上的蛋白質(zhì)，活化后從胞質(zhì)轉(zhuǎn)位至胞核,，通過(guò)識(shí)別和結(jié)合基因啟動(dòng)子區(qū)的順式作用元件,啟動(dòng)和調(diào)控基因表達(dá),。已知眾多的轉(zhuǎn)錄因子調(diào)節(jié)了自然殺傷(NK)細(xì)胞的發(fā)育,，但是到目前為止，它們的精確功能還不十分明確,。
在該研究中,，研究人員利用全局基因表達(dá)及全基因組關(guān)聯(lián)分析,，并結(jié)合發(fā)育及功能研究，揭示了NK細(xì)胞中ETS1轉(zhuǎn)錄因子的三種作用,。
研究發(fā)現(xiàn)，ETS1作用于NK細(xì)胞發(fā)育的早期階段,，并促進(jìn)以下蛋白分子的表達(dá)：關(guān)鍵性的轉(zhuǎn)錄調(diào)節(jié)因子（包括T-BET及ID2），NK細(xì)胞受體(NKRs)（包括NKp46,、Ly49H及Ly49D），以及對(duì)NKR功能必需的信號(hào)分子,。因此,，在刺激激活NKRs以后,，Ets1-/- 的NK細(xì)胞不能成功脫粒。
盡管如此,，這些細(xì)胞對(duì)細(xì)胞因子是高度靈敏的，并具有慢性刺激的特性,，包括NKRs以及多種激活相關(guān)基因的增強(qiáng)表達(dá)。
所以,，ETS1調(diào)節(jié)NK細(xì)胞內(nèi)廣泛的基因表達(dá)程序，促進(jìn)靶細(xì)胞的識(shí)別,，同時(shí)限制細(xì)胞因子誘導(dǎo)的激活作用。（生物谷Deepblue編譯）
doi: 10.1016/j.immuni.2012.04.006
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PMID:
Gene Deregulation and Chronic Activation in Natural Killer Cells Deficient in the Transcription Factor ETS1
Kevin Ramirez, Katherine J. Chandler, Christina Spaulding, Sasan Zandi, Mikael Sigvardsson, Barbara J. Graves, Barbara L. Kee.
Multiple transcription factors guide the development of mature functional natural killer (NK) cells, yet little is known about their function.We used global gene expression and genome-wide binding analyses combined with developmental and functional studies to unveil three roles for the ETS1 transcription factor in NK cells.ETS1 functions at the earliest stages of NK cell development to promote expression of critical transcriptional regulators including T-BET and ID2, NK cell receptors (NKRs) including NKp46, Ly49H, and Ly49D, and signaling molecules essential for NKR function.As a consequence, Ets1?/? NK cells fail to degranulate after stimulation through activating NKRs. Nonetheless, these cells are hyperresponsive to cytokines and have characteristics of chronic stimulation including increased expression of inhibitory NKRs and multiple activation-associated genes.Therefore, ETS1 regulates a broad gene expression program in NK cells that promotes target cell recognition while limiting cytokine-driven activation.
