Natural killer cells orchestrate angiogenesis

Abstract

Abstract Tumor-associated angiogenesis is accompanied by immunosuppression mediated by tumor cells and the immune microenvironment. Similarly, embryo implantation in the uterus requires both angiogenesis and immunosuppression. Uterine natural killer (NK) cells promote immune tolerance for the allogenic invasion of the embryo during pregnancy. In these studies, we explore the mechanism of NK cell-mediated vascular remodeling. RNA sequencing demonstrates a subpopulation of uterine NK cells that are enriched for proangiogenic genes in the uterus during pregnancy. Ephrin-B2 is a receptor tyrosine kinase well known for promoting angiogenesis in cancer, however, the mechanism for ephrin-B2-mediated angiogenesis in the uterus is not known. NK cells were isolated from the uterus and spleen of mice. Isolated NK cells were characterized for the expression of ephrin-B2 by immunofluorescence and flow cytometry. We show that uterine, but not splenic, NK cells express ephrin-B2. Because uterine NK cells also mediate immunosuppression, uterine NK cells were probed for expression of cytotoxicity markers. Cytotoxic marker CD27 is significantly upregulated in conventional NK cells, but not tissue-resident NK cells. Our data show that tissue resident uterine NK cells express pro-angiogenic marker ephrin-B2 and that these cells are not cytotoxic. This describes a previously unsuspected function for NK cells.