Complementary roles of Fas-associated death domain (FADD) and receptor interacting protein kinase-3 (RIPK3) in T-cell homeostasis and antiviral immunity
Complementary roles of Fas-associated death domain (FADD) and receptor interacting protein kinase-3 (RIPK3) in T-cell homeostasis and antiviral immunity
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DOI：
10.1073/pnas.1102779108
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发表时间：
2011-09-13
影响因子：
11.1
通讯作者：
Walsh, Craig M.
中科院分区：
文献类型：
--
作者：
Lu, Jennifer V.;Weist, Brian M.;Walsh, Craig M.
Caspase-8(caspase-8)是外源性细胞凋亡所必需的，casp8基因缺陷的小鼠不能在子宫内发育和死亡，最终也不能维持T细胞、B细胞和其他类型细胞的增殖。矛盾的是，这些失败并不是由细胞凋亡的缺陷引起的，而是由这种蛋白酶的一种假定的增殖功能引起的。事实上，在有丝分裂刺激后，缺乏casp8或其接头蛋白FADD(Fas相关死亡结构域蛋白)的T细胞会发展成高度自噬的形态，并死于一种被称为坏死性下垂的程序性坏死样死亡过程。最近的研究表明，受体相互作用蛋白激酶(RIPKs)RIPK1和RIPK3共同促进肿瘤坏死因子诱导的坏死性下垂，但RIPKs在缺乏FADD或casp8活性的T细胞死亡中的确切作用尚不清楚。在这里，我们证明了RIPK3和FADD在促进T细胞克隆性增殖和动态平衡方面具有相反和互补的作用。我们证明，携带干扰形式的FADD(FADDdd)的T细胞的缺陷增殖可以通过与RIPK3(-/-)小鼠杂交来挽救，尽管这种挽救最终会导致淋巴病变。刺激后这些双突变T细胞的增强恢复表明，FADD、casp8和RIPK3都是克隆性扩张、收缩和抗病毒反应所必需的。最后，我们证明了在面对死亡受体信号时，caspase介导的含有RIPK1的坏死诱导复合体(核小体)的切割足以防止坏死性下垂。这些研究突出了casp8活性的“两面性”，在某些情况下促进克隆扩张，在另一些情况下促进细胞凋亡。
Caspase-8 (casp8) is required for extrinsic apoptosis, and mice deficient in casp8 fail to develop and die in utero while ultimately failing to maintain the proliferation of T cells, B cells, and a host of other cell types. Paradoxically, these failures are not caused by a defect in apoptosis, but by a presumed proliferative function of this protease. Indeed, following mitogenic stimulation, T cells lacking casp8 or its adaptor protein FADD (Fas-associated death domain protein) develop a hyperautophagic morphology, and die a programmed necrosis-like death process termed necroptosis. Recent studies have demonstrated that receptor-interacting protein kinases (RIPKs) RIPK1 and RIPK3 together facilitate TNF-induced necroptosis, but the precise role of RIPKs in the demise of T cells lacking FADD or casp8 activity is unknown. Here we demonstrate that RIPK3 and FADD have opposing and complementary roles in promoting T-cell clonal expansion and homeostasis. We show that the defective proliferation of T cells bearing an interfering form of FADD (FADDdd) is rescued by crossing with RIPK3(-/-) mice, although such rescue ultimately leads to lymphadenopathy. Enhanced recovery of these double-mutant T cells following stimulation demonstrates that FADD, casp8, and RIPK3 are all essential for clonal expansion, contraction, and antiviral responses. Finally, we demonstrate that caspase-mediated cleavage of RIPK1-containing necrosis inducing complexes (necrosomes) is sufficient to prevent necroptosis in the face of death receptor signaling. These studies highlight the "two-faced" nature of casp8 activity, promoting clonal expansion in some situations and apoptotic demise in others.