The proapoptotic factors Bax and Bak regulate T cell proliferation through control of endoplasmic reticulum Ca2+ homeostasis
The proapoptotic factors Bax and Bak regulate T cell proliferation through control of endoplasmic reticulum Ca2+ homeostasis
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DOI：
10.1016/j.immuni.2007.05.023
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发表时间：
2007-08-01
期刊：
影响因子：
32.4
通讯作者：
Thompson, Craig B.
中科院分区：
文献类型：
--
作者：
Jones, Russell G.;Bui, Thi;Thompson, Craig B.
Bcl-2相关X蛋白（Bax）和Bcl-2拮抗剂/杀伤剂（巴克）是淋巴细胞凋亡的重要调节因子，但它们是否在活性T细胞功能中发挥作用仍不清楚。在这里，我们报告说，T细胞缺乏Bax和巴克显示缺陷的抗原特异性增殖，因为Ca 2+信号转导缺陷。Bax（-/-）、巴克（-/-）T细胞表现出缺陷的T细胞受体（TCR）和肌醇-1，4，5-三磷酸（IP 3）依赖性Ca 2+动员，这是因为改变了内质网（ER）Ca 2+调节，而Bax的重新引入逆转了这种调节。TCR依赖性Ca 2+信号刺激线粒体NADH产生超过ATIP合成的能力依赖于Bax和巴克。在Bax和巴克不存在的情况下，Ca 2+诱导的线粒体NADH升高的钝化导致T细胞增殖所需的活性氧产生减少。总之，数据确定Bax和巴克通过调节ER Ca 2+释放在控制T细胞增殖中起重要作用。
The Bcl-2-associated X protein (Bax) and Bcl-2-antagonist/killer (Bak) are essential regulators of lymphocyte apoptosis, but whether they play a role in viable T cell function remains unclear. Here, we report that T cells lacking both Bax and Bak display defects in antigen-specific proliferation because of Ca2+-signaling defects. Bax(-/-), Bak(-/-) T cells displayed defective T cell receptor (TCR)- and inositol-1,4,5-trisphosphate (IP3)-dependent Ca2+ mobilization because of altered endoplasmic reticulum (ER) Ca2+ regulation that was reversed by Bax's reintroduction. The ability of TCR-dependent Ca2+ signals to stimulate mitochondrial NADH production in excess of that utilized for ATIP synthesis was dependent on Bax and Bak. Blunting of Ca2+-induced mitochondrial NADH elevation in the absence of Bax and Bak resulted in decreased reactive-oxygen-species production, which was required for T cell proliferation. Together, the data establish that Bax and Bak play an essential role in the control of T cell proliferation by modulating ER Ca2+ release.