Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Physician-Scientist Development
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • In-Press Preview
    • Resource and Technical Advances
    • Clinical Research and Public Health
    • Research Letters
    • Editorials
    • Perspectives
    • Physician-Scientist Development
    • Reviews
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Resource and Technical Advances
  • Clinical Research and Public Health
  • Research Letters
  • Editorials
  • Perspectives
  • Physician-Scientist Development
  • Reviews
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Transfers
  • Advertising
  • Job board
  • Contact
Regulatory T cells are paramount effectors in progesterone regulation of embryo implantation and fetal growth
Ella S. Green, Lachlan M. Moldenhauer, Holly M. Groome, David J. Sharkey, Peck Y. Chin, Alison S. Care, Rebecca L. Robker, Shaun R. McColl, Sarah A. Robertson
Ella S. Green, Lachlan M. Moldenhauer, Holly M. Groome, David J. Sharkey, Peck Y. Chin, Alison S. Care, Rebecca L. Robker, Shaun R. McColl, Sarah A. Robertson
View: Text | PDF
Research Article Reproductive biology

Regulatory T cells are paramount effectors in progesterone regulation of embryo implantation and fetal growth

  • Text
  • PDF
Abstract

Progesterone (P4) is essential for embryo implantation, but the extent to which the pro-gestational effects of P4 depend on the maternal immune compartment is unknown. Here, we investigate whether regulatory T cells (Treg cells) act to mediate luteal phase P4 effects on uterine receptivity in mice. P4 antagonist RU486 administered to mice on days 1.5 and 3.5 postcoitum to model luteal phase P4 deficiency caused fewer CD4+Foxp3+ Treg cells and impaired Treg functional competence, along with dysfunctional uterine vascular remodeling and perturbed placental development in midgestation. These effects were linked with fetal loss and fetal growth restriction, accompanied by a Th1/CD8-skewed T cell profile. Adoptive transfer at implantation of Treg cells — but not conventional T cells — alleviated fetal loss and fetal growth restriction by mitigating adverse effects of reduced P4 signaling on uterine blood vessel remodeling and placental structure and by restoring maternal T cell imbalance. These findings demonstrate an essential role for Treg cells in mediating P4 effects at implantation and indicate that Treg cells are a sensitive and critical effector mechanism through which P4 drives uterine receptivity to support robust placental development and fetal growth.

Authors

Ella S. Green, Lachlan M. Moldenhauer, Holly M. Groome, David J. Sharkey, Peck Y. Chin, Alison S. Care, Rebecca L. Robker, Shaun R. McColl, Sarah A. Robertson

×

Figure 1

Impaired luteal phase P4 signaling causes fetal loss and fetal growth restriction in late gestation.

Options: View larger image (or click on image) Download as PowerPoint
Impaired luteal phase P4 signaling causes fetal loss and fetal growth re...
Female C57BL/6 (B6) mice were mated to BALB/c males and administered RU486 (1 mg/kg) or vehicle (control) on 1.5 and 3.5 dpc. Pregnancy and fetal outcomes were assessed in treated mice at 9.5 and 18.5 dpc and at birth. (A) Schematic of experimental design. (B) Pregnancy rate (% mated mice with ≥1 implantation site at 9.5 dpc or fetus at 18.5 dpc). (C) Number of normal implantation sites or viable fetuses per pregnant dam, number of abnormal or resorbing implantation sites (fetal losses) per pregnant dam, and fetal viability as percentage total implantation sites per pregnant dam were measured. See Supplemental Figure 1 for images of uteri recovered at 9.5 dpc. (D) Representative photomicrographs of viable implantation sites from control pregnant dams and abnormal implantation sites from RU486-treated dams on 9.5 dpc, stained with Masson’s trichrome. Asterisk indicates decidua. Pound sign indicates degenerating fetal tissue. Scale bar = 1 mm. See Supplemental Figure 2 for additional histology of implantation sites. (E) RU486-treated dams exhibit an elevated fetal resorption rate on 18.5 dpc. Resorption sites are indicated by arrows; letter C indicates cervix. Scale bar = 20 mm. (F) Fetuses of RU486-treated dams are visibly growth restricted. Scale bar = 12 mm. (G) Fetal and placental weights and fetal weight/placental weight ratios were measured in viable fetuses on 18.5 dpc. (H) In a separate cohort, mice were allowed to deliver, and number of viable pups per dam was quantified. For panels B, C, G, and H, treatment group is indicated in legend. (B) n = 36–49 mated females/group; data analyzed by χ2 test. (C and H) n = 9–16 pregnant dams/group; data shown as mean ± SEM with individual mice indicated by symbols, analyzed by unpaired t test; (G) n = 70–110 fetuses or placentas/group; data shown as violin plots with median and quartile values marked, analyzed by linear mixed model ANOVA with mother as subject. *P < 0.05, **P < 0.01, ***P < 0.001.

Copyright © 2026 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts