The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection.
The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection.
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DOI：
10.1084/jem.20150186
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发表时间：
2015-11-16
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影响因子：
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通讯作者：
Kaech SM
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文献类型：
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作者：
Dominguez CX;Amezquita RA;Guan T;Marshall HD;Joshi NS;Kleinstein SH;Kaech SM
多明格斯等人表明，大量的T - bet会在淋巴细胞性脉络丛脑膜炎病毒（LMCV）特异性细胞毒性T淋巴细胞（CTL）中诱导转录因子Zeb2。这些转录因子协同作用以限制记忆程序并驱动终末效应基因表达。
转录因子T - bet对细胞毒性T淋巴细胞（CTL）的分化至关重要，但在病毒感染期间它如何以分级方式在终末效应细胞和记忆前体细胞的形成中发挥作用尚不清楚。我们发现，在高浓度时，T - bet诱导Zeb2信使核糖核酸（mRNA）的表达，进而促使CTL进入终末分化状态。ZEB2和T - bet协同开启一个终末CTL分化程序，同时抑制中枢记忆性CTL发育所必需的基因。染色质免疫沉淀测序显示，这些基因中有很大一部分被T - bet结合，并且这种结合因ZEB2缺失而改变。此外，T - bet的过表达不能完全绕过ZEB2的功能。因此，T - bet和ZEB2的协同作用勾勒出一种新的遗传途径，该途径促使CTL向终末分化定向，从而限制了它们形成记忆细胞的潜能。
Dominguez et al. show that high amounts of T-bet induce the transcription factor Zeb2 in LMCV-specific CTLs. These transcription factors act in concert to restrict the memory program and drive terminal effector gene expression. The transcription factor T-bet is critical for cytotoxic T lymphocyte (CTL) differentiation, but it is unclear how it operates in a graded manner in the formation of both terminal effector and memory precursor cells during viral infection. We find that, at high concentrations, T-bet induced expression of Zeb2 mRNA, which then triggered CTLs to adopt terminally differentiated states. ZEB2 and T-bet cooperate to switch on a terminal CTL differentiation program, while simultaneously repressing genes necessary for central memory CTL development. Chromatin immunoprecipitation sequencing showed that a large proportion of these genes were bound by T-bet, and this binding was altered by ZEB2 deficiency. Furthermore, T-bet overexpression could not fully bypass ZEB2 function. Thus, the coordinated actions of T-bet and ZEB2 outline a novel genetic pathway that forces commitment of CTLs to terminal differentiation, thereby restricting their memory cell potential.