The requirements for fas-associated death domain signaling in mature T cell activation and survival
The requirements for fas-associated death domain signaling in mature T cell activation and survival
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DOI：
10.4049/jimmunol.171.1.247
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发表时间：
2003-07-01
影响因子：
4.4
通讯作者：
Walsh, CM
中科院分区：
文献类型：
--
作者：
Beisner, DR;Chu, IH;Walsh, CM
Fas相关死亡结构域(FADD)是一个含有死亡受体诱导细胞凋亡所需的细胞质适配分子的死亡结构域。矛盾的是，FADD在T细胞的发育和增殖中也起着至关重要的作用。使用表达FADD显性阴性形式(FADDdd)的小鼠的T细胞，抗TCR抗体和共刺激或外源细胞因子的激活作用大大降低。在转导相同转基因的野生型初级T细胞中也可以看到这一点，表明正常分化的T细胞需要FADD信号。有缺陷的增殖似乎与TCR刺激相关的早期事件无关。相反，随着FADD信号的阻断，受刺激的T细胞表现出与细胞分裂的启动相对应的高细胞死亡率。虽然CD4T细胞表现出中等程度的缺陷，但这种影响在CD8T细胞中最为明显。在体内，这种缺陷聚集的程度是最明显的；淋巴细胞性脉络膜脑膜炎病毒感染的FADDdd表达的小鼠完全无法产生抗原特异性反应。这些结果表明，在高度调控的方式下，FADD和最有可能的caspase可以传递生存信号或直接导致细胞凋亡，这些相反结果之间的平衡对获得性免疫至关重要。
Fas-associated death domain (FADD) is a death domain containing cytoplasmic adapter molecule required for the induction of apoptosis by death receptors. Paradoxically, FADD also plays a crucial role in the development and proliferation of T cells. Using T cells from mice expressing a dominant negative form of FADD (FADDdd), activation with anti-TCR Ab and costimulation or exogenous cytokines is profoundly diminished. This is also seen in wild-type primary T cells transduced with the same transgene, demonstrating that FADD signaling is required in normally differentiated T cells. The defective proliferation does not appear to be related to the early events associated with TCR stimulation. Rather, with a block in FADD signaling, stimulated T cells exhibit a high rate of cell death corresponding to the initiation of cell division. Although CD4 T cells exhibit a moderate deficiency, this effect is most profound in CD8 T cells. In vivo, the extent of this defective accumulation is most apparent; lymphocytic choriomenigitis virus-infected FADDdd-expressing mice completely fail to mount an Ag-specific response. These results show that, in a highly regulated fashion, FADD, and most likely caspases, can transduce either a signal for survival or one that leads directly to apoptosis and that the balance between these opposing outcomes is crucial to adaptive immunity.