Research ArticleNK CELLS

Gab3 is required for IL-2– and IL-15–induced NK cell expansion and limits trophoblast invasion during pregnancy

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Science Immunology  02 Aug 2019:
Vol. 4, Issue 38, eaav3866
DOI: 10.1126/sciimmunol.aav3866

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Gab3 adaptor prevents NK cell dysfunction

Natural killer (NK) cells are innate effector cells that help defend mammals from viral infections and cancer while acting locally in the uterus to support successful pregnancy outcomes. Sliz et al. used a chemical mutagenesis screen in mice to identify Gab3 as a scaffolding protein required for NK cell priming and peripheral expansion in response to cytokines. Gab3 mutant mice exhibited defects in their ability to control tumors and successfully complete pregnancies because of impaired NK cell function. This study identifies an adaptor protein required to achieve full NK cell function and enhances our understanding of how subtle uterine NK cell perturbations can contribute to the demise of pregnancies. See related Focus by Colucci.

Abstract

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.

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