VEGF C facilitates immune tolerance and endovascular activity of human uterine NK cells at the maternal-fetal interface

• Published in: The Journal of immunology (1950) 2009-04, Vol.182 (7), p.4085-4092
• Main Authors: Kalkunte, Satyan S., Mselle, Teddy F., Norris, Wendy E., Wira, Charles R., Sentman, Charles L., Sharma, Surendra
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0803769

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. Here we demonstrate that VEGF C, a pro-angiogenic factor produced by uNK cells, is responsible for their non-cytotoxic activity. VEGF C-producing uNK cells support endovascular processes as demonstrated in a three dimensional co-culture 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 “transporter associated with antigen processing (TAP)-1” expression and MHC class I assembly in target cells. siRNA-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 non-cytotoxic. This phenotype is critical to their pregnancy compatible immuno-vascular role during placentation and fetal development.