Progesterone and HMOX-1 promote fetal growth by [CD8.sup.+] T cell modulation

Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies in Western societies. IUGR is a strong predictor of reduced short-term neonatal survival and impairs long-term health in children. Placental insufficiency is often associated with IUGR; however, the molecular mechanisms involved in the pathogenesis of placental insufficiency and IUGR are largely unknown. Here, we developed a mouse model of fetal-growth restriction and placental insufficiency that is induced by a midgestational stress challenge. Compared with control animals, pregnant dams subjected to gestational stress exhibited reduced progesterone levels and placental heme oxygenase 1 (Hmox1) expression and increased methylation at distinct regions of the placental Hmox1 promoter. These stress-triggered changes were accompanied by an altered [CD8.sup.+] T cell response, as evidenced by a reduction of tolerogenic [CD8.sup.+][CD122.sup.+] T cells and an increase of cytotoxic [CD8.sup.+] T cells. Using progesterone receptor- or Hmox1-deficient mice, we identified progesterone as an upstream modulator of placental Hmox1 expression. Supplementation of progesterone or depletion of [CD8.sup.+] T cells revealed that progesterone suppresses [CD8.sup.+] T cell cytotoxicity, whereas the generation of [CD8.sup.+][CD122.sup.+] T cells is supported by Hmox1 and ameliorates fetal- growth restriction in Hmox1 deficiency. These observations in mice could promote the identification of pregnancies at risk for IUGR and the generation of clinical interventional strategies.