Histone Deacetylase 7 Regulates Cell Survival and TCR Signaling in CD4/CD8 Double-Positive Thymocytes
Histone Deacetylase 7 Regulates Cell Survival and TCR Signaling in CD4/CD8 Double-Positive Thymocytes
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DOI：
10.4049/jimmunol.1001179
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发表时间：
2011-04-15
影响因子：
4.4
通讯作者：
Verdin, Eric
中科院分区：
文献类型：
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作者：
Kasler, Herbert G.;Young, Bryan D.;Verdin, Eric
CD 4/CD 8双阳性胸腺细胞表达转录阻遏物组蛋白脱乙酰酶（HDAC）7，一种在TCR接合后从细胞核输出的IIa类HDAC。通过信号依赖性核输出，IIa类HDACs如HDAC 7介导基因表达的信号依赖性变化，这对多种组织中的发育命运决定很重要。我们报告说，HDAC 7在小鼠胸腺细胞的阳性选择过程中从细胞核中输出，它调节基因介导TCR接合和下游事件之间的耦合，决定细胞存活。缺乏HDAC 7的胸腺细胞由于寿命严重缩短而被低效地积极选择，并表现出TCR J α区段的截短库。在HDAC 7缺陷型胸腺细胞中，对TCR接合的应答的多种重要介质和调节剂的表达发生改变，导致观察到的活力丧失的强直性MAPK活性增加。值得注意的是，蛋白激酶D的活性，介导的HDAC 7的核输出响应TCR信号传导的激酶，也增加了HDAC 7缺陷的胸腺细胞，这表明HDAC 7核输出控制自我维持的自兴奋环。这些实验增加了对胸腺T细胞发育中的生/死决定的理解，定义了IIa类HDAC的新功能，并指出了一种新的前馈机制，这些分子借此调节自身状态并介导稳定的发育转变。免疫学杂志，2011，186：4782-4793。
CD4/CD8 double-positive thymocytes express the transcriptional repressor histone deacetylase (HDAC) 7, a class IIa HDAC that is exported from the cell nucleus after TCR engagement. Through signal-dependent nuclear export, class IIa HDACs such as HDAC7 mediate signal-dependent changes in gene expression that are important to developmental fate decisions in multiple tissues. We report that HDAC7 is exported from the cell nucleus during positive selection in mouse thymocytes and that it regulates genes mediating the coupling between TCR engagement and downstream events that determine cell survival. Thymocytes lacking HDAC7 are inefficiently positively selected due to a severely shortened lifespan and exhibit a truncated repertoire of TCR J alpha segments. The expression of multiple important mediators and modulators of the response to TCR engagement is altered in HDAC7-deficient thymocytes, resulting in increased tonic MAPK activity that contributes to the observed loss of viability. Remarkably, the activity of protein kinase D, the kinase that mediates nuclear export of HDAC7 in response to TCR signaling, is also increased in HDAC7-deficient thymocytes, suggesting that HDAC7 nuclear export governs a self-sustaining autoexcitatory loop. These experiments add to the understanding of the life/death decision in thymic T cell development, define a novel function for class IIa HDACs, and point to a novel feed-forward mechanism whereby these molecules regulate their own state and mediate stable developmental transitions. The Journal of Immunology, 2011, 186: 4782-4793.