The GRB2-associated binding protein 3 is required for IL-2 and IL-15 induced NK cell expansion and limits trophoblast invasion during pregnancy

The Grb2-associated binding protein 3 (Gab3) is a scaffolding protein that belongs to the Grb2-assocated binding family of proteins along with Gab1 and Gab2. Gab3 is expressed exclusively in immune cells including NK cells, CD8+T cells, mast cells and macrophages, however the function of Gab3 has remained elusive. Based on two independent mouse models; a hypomorph germline mouse model carrying a missense mutation in the PH domain of Gab3 and complete Gab3-KO mice, we uncovered a key role for Gab3 in peripheral NK cell function. Specifically, loss of Gab3 results in impaired IL-2/IL-15-induced NK cell priming and expansion, due to a selective impairment in MAPK- but not STAT5-signaling. In vivo, we show that Gab3 is required for recognition and elimination of “missing-self” and tumor targets. Gab3-deficient mice exhibit impaired uterine NK cell expansion that is associated with abnormal spiral artery remodeling and increased trophoblast invasion in the decidua basalis. This coincides with stillbirth, retained placenta, maternal hemorrhage and undelivered fetoplacental units at term. Thus, our studies identify Gab3 as a novel component required for IL-2/IL-15-mediated NK cell priming and expansion that is essential for anti-tumor responses and for controlling fetal trophoblast invasion during pregnancy.