The caspase 8 inhibitor c-FLIPL modulates T-cell receptor-induced proliferation but not activation-induced cell death of lymphocytes
The caspase 8 inhibitor c-FLIPL modulates T-cell receptor-induced proliferation but not activation-induced cell death of lymphocytes
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DOI：
10.1128/mcb.22.15.5419-5433.2002
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发表时间：
2002-08-01
影响因子：
5.3
通讯作者：
Tschopp, J
中科院分区：
文献类型：
--
作者：
Lens, SMA;Kataoka, T;Tschopp, J
半胱天冬酶8抑制剂c-FLIPL可以在体外作为细胞死亡和死亡受体Fas（CD 95）传递的生长信号之间的分子开关。为了阐明其在体内的功能，产生了在T细胞区室中过表达c-FLIPL的转基因小鼠（c-FLIPL Tg小鼠）。正如预期的那样，FasL诱导的细胞凋亡在来自c-FLIPL Tg小鼠的T细胞中被抑制。相比之下，c-FLIPL Tg小鼠中T细胞的活化诱导的细胞死亡不受影响，这表明该缺失过程可以在不存在活性半胱天冬酶8的情况下进行。因此，c-FLIPL Tg小鼠与Fas缺陷小鼠的不同之处在于没有B220（+）CD 4（-）CD 8（-）T细胞的蓄积。然而，用次优剂量的抗CD 3或抗原刺激T淋巴细胞显示来自c-FLIPL Tg小鼠的T细胞中的增殖反应增加。因此，c-FLIPL在体内的主要作用是通过降低T细胞受体信号传导阈值来调节T细胞增殖。
The caspase 8 inhibitor c-FLIPL can act in vitro as a molecular switch between cell death and growth signals transmitted by the death receptor Fas (CD95). To elucidate its function in vivo, transgenic mice were generated that overexpress c-FLIPL in the T-cell compartment (c-FLIPL Tg mice). As anticipated, FasL-induced apoptosis was inhibited in T cells from the c-FLIPL Tg mice. In contrast, activation-induced cell death of T cells in c-FLIPL Tg mice was unaffected, suggesting that this deletion process can proceed in the absence of active caspase 8. Accordingly, c-FLIPL Tg mice differed from Fas-deficient mice by showing no accumulation of B220(+) CD4(-) CD8(-) T cells. However, stimulation of T lymphocytes with suboptimal doses of anti-CD3 or antigen revealed increased proliferative responses in T cells from c-FLIPL Tg mice. Thus, a major role of c-FLIPL in vivo is the modulation of T-cell proliferation by decreasing the T-cell receptor signaling threshold.