Interferon g Contributes to Initiation of Uterine Vascular Modification, Decidual Integrity, and Uterine Natural Killer Cell Maturation during Normal Murine Pregnancy

The dominant lymphocytes in human and murine implantation sites are transient, pregnancyassociated uterine natural killer (uNK) cells. These cells are a major source of interferon (IFN)g . Implantation sites in mice lacking uNK cells (alymphoid recombinase activating gene [RAG]2 2 / 2 common cytokine receptor chain g [ g c ] 2 / 2 ) or IFNg signaling (IFNg 2 / 2 or IFNg R a 2 / 2 ) fail to initiate normal pregnancy-induced modification of decidual arteries and display hypocellularity or necrosis of decidua. To investigate the functions of uNK cell–derived IFNg during pregnancy, RAG-2 2 / 2 g c 2 / 2 females were engrafted with bone marrow from IFNg 2 / 2 mice, IFNg signal-disrupted mice (IFNg R a 2 / 2 or signal transducer and activator of transcription [Stat]-1 2 / 2 ), or from mice able to establish normal uNK cells (severe combined immunodeficient [SCID] or C57BL/6). Mated recipients were analyzed at midgestation. All grafts established uNK cells. Grafts from IFNg 2 / 2 mice did not reverse host vascular or decidual pathology. Grafts from all other donors promoted modification of decidual arteries and decidual cellularity. Grafts from IFNg R a 2 / 2 or Stat-1 2 / 2 mice overproduced uNK cells, all of which were immature. Grafts from IFNg 2 / 2 , SCID, or C57BL/6 mice produced normal, mature uNK cells. Administration of murine recombinant IFNg to pregnant RAG-2 2 / 2 g c 2 / 2 mice initiated decidual vessel modification and promoted decidual cellularity in the absence of uNK cells. These in vivo findings strongly suggest that uNK cell–derived IFNg modifies the expression of genes in the uterine vasculature and stroma, which initiates vessel instability and facilitates pregnancy-induced remodeling of decidual arteries.