Transcriptional repressor ZEB2 promotes terminal differentiation of CD8+ effector and memory T cell populations during infection.
Transcriptional repressor ZEB2 promotes terminal differentiation of CD8+ effector and memory T cell populations during infection.
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DOI：
10.1084/jem.20150194
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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：
Goldrath AW
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文献类型：
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作者：
Omilusik KD;Best JA;Yu B;Goossens S;Weidemann A;Nguyen JV;Seuntjens E;Stryjewska A;Zweier C;Roychoudhuri R;Gattinoni L;Bird LM;Higashi Y;Kondoh H;Huylebroeck D;Haigh J;Goldrath AW
在病毒感染的反应中，活化的CD8+ T细胞分化为末端效应T细胞和记忆T细胞。这个发育过程是由转录抑制因子Zeb2控制的，它作用于T-bet的下游。ZEB2是一种多锌指转录因子，已知在早期神经发生和上皮-间质过渡依赖性肿瘤转移中发挥重要作用。虽然ZEB2在T淋巴细胞中的功能尚不清楚，但密切相关的家族成员ZEB1的活性与淋巴细胞发育有关。在这里，我们发现活化的T细胞上调ZEB2的表达，特别是在KLRG1hi效应的CD8+ T细胞亚群中。在原发性和继发性感染后，ZEB2表达的缺失导致抗原特异性CD8+ T细胞的显著缺失，严重损害KLRG1hi效应记忆细胞群的产生。我们发现，ZEB2可以在串联、一致的E-box位点结合DNA，调节几个e蛋白靶点的基因表达，并可能直接抑制CD8+ T细胞对感染的Il7r和Il2。此外，我们发现T-bet结合到Zeb2基因中高度保守的T-box位点，并且T-bet和Zeb2在效应T细胞中调控相似的基因表达程序，这表明T-bet通过调控Zeb2上游发挥作用。总的来说，我们将ZEB2置于一个更大的转录网络中，该网络负责终端分化和记忆性CD8+ T细胞形成之间的平衡。
In response to viral infections, activated CD8+ T cells differentiate into terminal effector and memory T cells. This developmental process is controlled by the transcriptional repressor Zeb2, which acts downstream of T-bet. ZEB2 is a multi-zinc-finger transcription factor known to play a significant role in early neurogenesis and in epithelial-mesenchymal transition–dependent tumor metastasis. Although the function of ZEB2 in T lymphocytes is unknown, activity of the closely related family member ZEB1 has been implicated in lymphocyte development. Here, we find that ZEB2 expression is up-regulated by activated T cells, specifically in the KLRG1hi effector CD8+ T cell subset. Loss of ZEB2 expression results in a significant loss of antigen-specific CD8+ T cells after primary and secondary infection with a severe impairment in the generation of the KLRG1hi effector memory cell population. We show that ZEB2, which can bind DNA at tandem, consensus E-box sites, regulates gene expression of several E-protein targets and may directly repress Il7r and Il2 in CD8+ T cells responding to infection. Furthermore, we find that T-bet binds to highly conserved T-box sites in the Zeb2 gene and that T-bet and ZEB2 regulate similar gene expression programs in effector T cells, suggesting that T-bet acts upstream and through regulation of ZEB2. Collectively, we place ZEB2 in a larger transcriptional network that is responsible for the balance between terminal differentiation and formation of memory CD8+ T cells.