Andjelic S, Liou H C
Department of Medicine, Division of Immunology, Cornell University Medical College, New York 10021, USA.
Eur J Immunol. 1998 Feb;28(2):570-81. doi: 10.1002/(SICI)1521-4141(199802)28:02<570::AID-IMMU570>3.0.CO;2-M.
An extensive body of data, in a variety of systems, denoted the caspase family of proteases as a key player in the execution of programmed cell death. This family consists of cysteine proteases that cleave after asparagine-containing motifs. It is well established that the caspases are essential for the apoptosis mediated by Fas (CD95) and TNF receptor p55, molecules that contain the "death domain" in the cytoplasmic tail. However, little is known about the mechanisms underlying the antigen receptor-mediated cell death in B lymphocytes, a process instrumental in negative selection of potentially autoreactive B cells. Here, we investigated the involvement of caspases in cell death triggered via the antigen receptor in B lymphocytes (BCR) by using specific inhibitors. Initially, we used a well-established cell line, CH31, which is a model of B cell tolerance, to demonstrate that these proteases indeed participate in the BCR-induced apoptotic pathway. Next, we confirmed the physiological relevance of the caspase-mediated cell death pathway in splenic B cell populations isolated ex vivo that were induced to undergo apoptosis by extensive cross-linking of their BCR. Most interestingly, our data demonstrated that caspases regulate not only the nuclear DNA fragmentation, but also the surface membrane phosphatidylserine translocation as well as the degradation of a specific nuclear substrate. Taken together, this report supports the hypothesis that regulation of the caspase family is crucial in controlling the life/death decision in B lymphocytes mediated by the antigen receptor signal transduction.
大量来自各种系统的数据表明，蛋白酶的半胱天冬酶家族是程序性细胞死亡执行过程中的关键参与者。该家族由在含天冬酰胺基序后切割的半胱氨酸蛋白酶组成。众所周知，半胱天冬酶对于由Fas（CD95）和TNF受体p55介导的凋亡至关重要，这些分子在细胞质尾部含有“死亡结构域”。然而，对于B淋巴细胞中抗原受体介导的细胞死亡的潜在机制知之甚少，这一过程在潜在自身反应性B细胞的阴性选择中起重要作用。在这里，我们通过使用特异性抑制剂研究了半胱天冬酶在B淋巴细胞（BCR）中通过抗原受体触发的细胞死亡中的作用。最初，我们使用一种成熟的细胞系CH31，它是B细胞耐受的模型，来证明这些蛋白酶确实参与了BCR诱导的凋亡途径。接下来，我们证实了半胱天冬酶介导的细胞死亡途径在体外分离的脾B细胞群体中的生理相关性，这些细胞通过广泛交联其BCR而被诱导发生凋亡。最有趣的是，我们的数据表明，半胱天冬酶不仅调节核DNA片段化，还调节表面膜磷脂酰丝氨酸易位以及特定核底物的降解。综上所述，本报告支持以下假设：半胱天冬酶家族的调节对于控制由抗原受体信号转导介导的B淋巴细胞的生死决定至关重要。
