The scaffolding protein Grb2-associated binding protein 3 (Gab3) is a member of the Gab family, whose functions have remained elusive. Here, we identify Gab3 as a key determinant of peripheral NK cell expansion. Loss of Gab3 resulted in impaired IL-2 and IL-15-induced NK cell priming and expansion due to a selective impairment in MAPK signaling but not STAT5 signaling. In vivo, we found that Gab3 is required for recognition and elimination of "missing-self" and tumor targets. Unexpectedly, our studies also revealed that Gab3 plays an important role during pregnancy. Gab3-deficient mice exhibited impaired uterine NK cell expansion associated with abnormal spiral artery remodeling and increased trophoblast invasion in the decidua basalis. This coincided with stillbirth, retained placenta, maternal hemorrhage, and undelivered fetoplacental units at term. Thus, Gab3 is a key component required for cytokine-mediated NK cell priming and expansion that is essential for antitumor responses and limits trophoblast cell invasion during pregnancy.

中文翻译：

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Gab3是IL-2-和IL-15诱导的NK细胞扩增所必需的，并限制了孕期滋养细胞的侵袭。

脚手架蛋白Grb2相关的结合蛋白3（Gab3）是Gab家族的成员，其功能仍然难以捉摸。在这里，我们确定Gab3是外周血NK细胞扩增的关键决定因素。由于MAPK信号传导而非STAT5信号传导的选择性损伤，Gab3的缺失导致IL-2和IL-15诱导的NK细胞启动和扩增受损。在体内，我们发现Gab3是识别和消除“失踪者”和肿瘤靶标所必需的。出乎意料的是，我们的研究还表明，Gab3在怀孕期间起着重要作用。缺乏Gab3的小鼠表现出子宫NK细胞扩增受损，与异常的螺旋动脉重塑相关，并增加了蜕膜基底膜中滋养细胞的侵袭。这与死产，胎盘滞留，产妇出血，足月胎盘和胎盘未交货单位。因此，Gab3是细胞因子介导的NK细胞启动和扩增所需的关键成分，对于抗肿瘤反应至关重要，并限制了妊娠期间滋养层细胞的入侵。