Vascular endothelial growth factor C facilitates immune tolerance and endovascular activity of human uterine NK cells at the maternal-fetal interface.
Although replete with cytotoxic machinery, uterine NK (uNK) cells remain tolerant at the maternal-fetal interface. The mechanisms that facilitate the uNK cell tolerance are largely unknown. In this study, we demonstrate that vascular endothelial growth factor (VEGF) C, a proangiogenic factor produced by uNK cells, is responsible for their noncytotoxic activity. VEGF C-producing uNK cells support endovascular processes as demonstrated in a three-dimensional coculture model of capillary tube formation on Matrigel. Peripheral blood NK cells fail to produce VEGF C and remain cytotoxic. This response can be reversed by exogenous VEGF C. We show that cytoprotection by VEGF C can be related to induction of the TAP-1 expression and MHC class I assembly in target cells. Small interfering RNA-mediated silencing of TAP-1 expression abolished the VEGF C-imparted protection. Overall, these results demonstrate that empowerment of uNK cells with angiogenic factors keeps them noncytotoxic. This phenotype is critical to their pregnancy-compatible immunovascular role during placentation and fetal development.
Kalkunte
Satyan S
SS
Department of Pediatrics, Women and Infants Hospital-Warren Alpert Medical School of Brown University, Providence, RI 02905, USA.
Mselle
Teddy F
TF
Norris
Wendy E
WE
Wira
Charles R
CR
Sentman
Charles L
CL
Sharma
Surendra
S
D000328:Adult; D015153:Blotting, Western; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D003656:Decidua / Q000166:cytology / Q000276:immunology*; D005260:Female; D005333:Fetus / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D018919:Neovascularization, Physiologic / Q000276:immunology; D011247:Pregnancy / Q000276:immunology*; D014599:Uterus / Q000276:immunology*; D042582:Vascular Endothelial Growth Factor C / Q000276:immunology* / Q000378:metabolism
C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C