Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1
Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1
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DOI：
10.1038/32681
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发表时间：
1998-03-19
期刊：
影响因子：
64.8
通讯作者：
Winoto, A
中科院分区：
文献类型：
--
作者：
Zhang, JK;Cado, D;Winoto, A
程序性细胞死亡或细胞凋亡在免疫系统的稳态中很重要：例如，无功能或自身反应性淋巴细胞通过细胞凋亡被消除。Fas（也称为CD95或Apo-1）可以触发细胞死亡，对淋巴细胞稳态至关重要（1,2）。FADD/Mort1（文献3-6）是一种pas相关蛋白，被认为通过募集蛋白酶caspase-8介导细胞凋亡（文献7,8）。FADD的显性阴性突变体抑制Fas和其他TNFR家族成员启动的细胞凋亡（6,9-14）。其他蛋白，尤其是Daax，也可以结合Fas并可能介导不依赖于Fas的凋亡通路（15）。在这里，我们通过产生FADD缺陷小鼠来研究FADD在体内的作用。由于纯合子小鼠在子宫内死亡，我们在缺乏重组激活基因rag1的背景下产生了FADD（-/-）胚胎干细胞和FADD（-/-）嵌合体，该基因可激活免疫球蛋白和t细胞受体基因的重排。我们发现，新生嵌合体的胸腺细胞亚群明显正常。Fas诱导的细胞凋亡被完全阻断，表明不存在多余的Fas凋亡途径。随着这些小鼠年龄的增长，它们的胸腺细胞减少到无法检测到的水平，尽管在所有老年FADD（-/-）嵌合体中存在外周T细胞，出乎意料的是，这些FADD(-/-) T细胞的激活诱导增殖受到损害，尽管产生细胞因子白细胞介素(IL)-2。这些结果以及FADD（-/-）小鼠与缺乏IL-2受体p亚基的小鼠之间的相似性表明，细胞增殖与凋亡之间存在意想不到的联系。
Programmed cell death, or apoptosis, is important in homeostasis of the immune system: for example, non-functional or autoreactive lymphocytes are eliminated through apoptosis, One member of the tumour necrosis factor receptor (TNFR) family; Fas (also known as CD95 or Apo-1), can trigger cell death and is essential for lymphocyte homeostasis(1,2). FADD/Mort1 (refs 3-6) is a Pas-associated protein that is thought to mediate apoptosis by recruiting the protease caspase-8 (refs 7, 8), A dominant-negative mutant of FADD inhibits apoptosis initiated by Fas and other TNFR family members(6,9-14). Other proteins, notably Daax, also bind Fas and presumably mediate a FADD-independent apoptotic pathway(15). Here we investigate the role of FADD in vivo by generating FADD-deficient mice. As homozygous mice die in utero, we generated FADD(-/-) embryonic stem cells and FADD(-/-) chimaeras in a background devoid of the recombination activating gene RAG-1, which activates rearrangement of the immunoglobulin and T-cell receptor genes, We found that thymocyte subpopulations were apparently normal in newborn chimaeras. Fas-induced apoptosis was completely blocked, indicating that there are no redundant Fas apoptotic pathways, As these mice age, their thymocytes decrease to an undetectable level, although peripheral T cells are present in all older FADD(-/-) chimaeras, Unexpectedly, activation-induced proliferation is impaired in these FADD(-/-) T cells, despite production of the cytokine interleukin (IL)-2, These results and the similarities between FADD(-/-) mice and mice lacking the P-subunit of the IL-2 receptor suggest that there is an unexpected connection between cell proliferation and apoptosis.