The PD-1/PD-L1 inhibitory pathway is altered in pre-eclampsia and regulates T cell responses in pre-eclamptic rats.
The programmed cell death-1(PD-1)/PD-ligand 1 (PD-L1) pathway is critical to immune homeostasis by promoting regulatory T (Treg) development and inhibiting effector T (such as Th17) cell responses. However, the association between the PD-1/PD-L1 pathway and the Treg/Th17 imbalance has not been fully investigated in pre-eclampsia (PE). In this study, we observed an inverse correlation between the percentages of Treg and Th17 cells, and the expression of PD-1 and PD-L1 on the two subsets also changed in PE compared with normal pregnancy. We further explored their relationship in vivo using the L-NG-Nitroarginine Methyl Ester (L-NAME) induced PE-like rat models, also characterized by Treg/Th17 imbalance. Administration of PD-L1-Fc protein provides a protective effects on the pre-eclamptic models, both to the mother and the fetuses, by reversing Treg/Th17 imbalance through inhibiting PI3K/AKT/m-TOR signaling and enhancing PTEN expression. In addition, we also observed a protective effect of PD-L1-Fc on the placenta by reversing placental damages. These results suggested that altered PD-1/PD-L1 pathway contributed to Treg/Th17 imbalance in PE. Treatment with PD-L1-Fc posed protective effects on pre-eclamptic models, indicating that the use of PD-L1-Fc might be a potential therapeutic target in PE treatment.
Family Planning Research Institute, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China.
Mei
M
Tian
Family Planning Research Institute, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China.
Yonghong
Y
Zhang
Family Planning Research Institute, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China.
Zhaozhao
Z
Liu
Department of Obstetrics and Gynecology, Maternal and Child Health Hospital of Hubei province, Wuhan, P.R. China.
Guoqiang
G
Sun
Department of Obstetrics, Gynecology &Reproductive Sciences, Division of Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
Gil
G
Mor
Family Planning Research Institute, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China.
Aihua
A
Liao
D000328:Adult; D000818:Animals; D060890:B7-H1 Antigen / Q000378:metabolism*; D005260:Female; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011225:Pre-Eclampsia / Q000097:blood / Q000378:metabolism*; D011247:Pregnancy; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000378:metabolism*
D060890:B7-H1 Antigen; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D061026:Programmed Cell Death 1 Receptor; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases