T cell-specific FADD-deficient mice: FADD is required for early T cell development
T cell-specific FADD-deficient mice: FADD is required for early T cell development
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DOI：
10.1073/pnas.111158698
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发表时间：
2001-05-22
影响因子：
11.1
通讯作者：
Winoto, A
中科院分区：
文献类型：
--
作者：
Kabra, NH;Kang, CH;Winoto, A
FADD/Mort 1最初被鉴定为Fas相关的死亡结构域蛋白，在由Fas、肿瘤坏死因子受体-I、DR 3和TRAIL受体启动的细胞凋亡中起衔接分子的作用。小鼠中的FADD无效突变是胚胎致死的，并且来自RAG-1（-/-）重建嵌合体的FADD（-/-）T细胞的分析表明FADD在成熟T细胞增殖中的作用。在这里，我们报告的T细胞特异性FADD缺陷小鼠通过条件基因组拯救方法的产生。我们发现FADD缺陷导致T细胞在CD 4（-）CD 8（-）阶段发育的抑制和成熟T细胞数量的减少。FADD突变不影响细胞凋亡或前T细胞受体的近端信号事件; T细胞受体转基因的引入不能挽救突变表型。这些数据表明FADD，通过含有死亡结构域的受体或新的受体非依赖性机制，是早期T细胞发育的增殖期所需的。
FADD/Mort1, initially identified as a Fas-associated death-domain containing protein, functions as an adapter molecule in apoptosis initiated by Fas, tumor necrosis factor receptor-I, DR3, and TRAIL-receptors, However, FADD likely participates in additional signaling cascades. FADD-null mutations in mice are embryonic-lethal, and analysis of FADD(-/-) T cells from RAG-1(-/-) reconstituted chimeras has suggested a role for FADD in proliferation of mature T cells. Here, we report the generation of T cell-specific FADD-deficient mice via a conditional genomic rescue approach. We find that FADD-deficiency leads to inhibition of T cell development at the CD4(-)CD8(-) stage and a reduction in the number of mature T cells, The FADD mutation does not affect apoptosis or the proximal signaling events of the pre-T cell receptor; introduction of a T cell receptor transgene fails to rescue the mutant phenotype, These data suggest that FADD, through either a death-domain containing receptor or a novel receptor-independent mechanism, is required for the proliferative phase of early T cell development.