Vascular endothelial growth factor C facilitates immune tolerance and endovascular activity of human uterine NK cells at the maternal-fetal interface

J Immunol. 2009 Apr 1;182(7):4085-92. doi: 10.4049/jimmunol.0803769.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Blotting, Western
  • Coculture Techniques
  • Cytotoxicity, Immunologic
  • Decidua / cytology
  • Decidua / immunology*
  • Female
  • Fetus / immunology
  • Flow Cytometry
  • Humans
  • Immune Tolerance / immunology*
  • Killer Cells, Natural / immunology*
  • Neovascularization, Physiologic / immunology
  • Pregnancy / immunology*
  • Uterus / immunology*
  • Vascular Endothelial Growth Factor C / immunology*
  • Vascular Endothelial Growth Factor C / metabolism

Substances

  • VEGFC protein, human
  • Vascular Endothelial Growth Factor C