Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation

J Clin Invest. 2015 Apr;125(4):1726-38. doi: 10.1172/JCI68140. Epub 2015 Mar 16.


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+ T cell response, as evidenced by a reduction of tolerogenic CD8+CD122+ T cells and an increase of cytotoxic CD8+ 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+ T cells revealed that progesterone suppresses CD8+ T cell cytotoxicity, whereas the generation of CD8+CD122+ 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • DNA Methylation
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Female
  • Fetal Development / physiology*
  • Fetal Growth Retardation / immunology
  • Fetal Growth Retardation / prevention & control*
  • Fetus / immunology
  • Fetus / pathology
  • Heme Oxygenase-1 / biosynthesis
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / physiology*
  • Male
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Noise / adverse effects
  • Placenta / immunology*
  • Placenta / metabolism
  • Placental Circulation
  • Placental Insufficiency / etiology
  • Placental Insufficiency / immunology*
  • Pregnancy
  • Pregnancy Complications / genetics
  • Pregnancy Complications / immunology*
  • Pregnancy Complications / psychology
  • Progesterone / biosynthesis
  • Progesterone / physiology*
  • Progesterone / therapeutic use
  • Promoter Regions, Genetic
  • RNA, Messenger / genetics
  • Stress, Psychological / genetics
  • Stress, Psychological / immunology*


  • Membrane Proteins
  • RNA, Messenger
  • Progesterone
  • Heme Oxygenase-1
  • Hmox1 protein, mouse