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Sci Immunol. 2019 Aug 2;4(38). pii: eaav3866. doi: 10.1126/sciimmunol.aav3866.

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

Author information

1
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA.
2
Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
3
Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA.
4
Biomedical Informatics Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA.
5
Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH 45267, USA.
6
Janssen R&D, Spring House, PA 19002, USA.
7
Division of General Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
8
Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA.
9
Janssen R&D, Spring House, PA 19002, USA. khoebe@its.jnj.com.

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.

PMID:
31375526
DOI:
10.1126/sciimmunol.aav3866

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