Cooperative actions of natural killer cells and invasive trophoblast cells at the uterine-placental interface

Abstract

Natural killer (NK) and invasive trophoblast (IT) cells facilitate the establishment of the uterine-placental interface by transforming the uterus into a hospitable site for fetal development. NK cells act first followed by IT cells. These dynamics are conserved in human and rat hemochorial placentation. Herein, we utilize mutant rat models to investigate contributions of NK and IT cells in establishment of the uterine-placental interface and pregnancy outcomes. NK and IT cell deficiencies were established by disruptions of interleukin 15 (Il15) and placenta specific 1 (Plac1) loci in rat, respectively. Pregnancies with homogenous placental genotypes/phenotypes were analyzed. Four different breeding combinations were used to generate wild type, NK cell deficient, IT cell deficient, and NK-IT cell double-deficient pregnancies. Pregnancies were examined on gestation days (gd) 7.5, 13.5, 15.5, and 18.5. Viability and uterine-placental interface integrity were determined using structural and molecular/biochemical approaches. Viability and litter size did not differ among the breeding combinations at gd 7.5. At gd 13.5 and 15.5, maternal NK cell deficiency was associated with an acceleration of deep endovascular IT cell invasion into the uterine-placental interface. PLAC1 deficiency resulted in placentomegaly and absence of intrauterine interstitial IT cells, which resulted in the retention/expansion of NK cells in the uterine-placental interface. Double-deficient pregnancies exhibited fetal growth restriction, a significant decrease in fetal survival, increased maternal mortality, and compromised postnatal offspring survival. These experiments highlight the cooperative roles of NK and IT cells in ensuring a healthy pregnancy. They work together to facilitate uterine vascular remodeling and the essential delivery of nutrients to the placenta and fetus for a successful pregnancy outcome. Failures in the collective contributions of NK and IT cells adversely affect plasticity and lead to disease states associated with placentation, fetal development, and maternal wellbeing.