Prevention of CpG-induced pregnancy disruption by adoptive transfer of in vitro-induced regulatory T cells.
OBJECTIVE
To elucidate the mechanism by which embryo-resorption and preterm birth were enhanced by pathogenic CpG motif and to develop a counter strategy for normal pregnancy outcome.


METHODS
This is an animal model-based study. In pregnant nonobese diabetic (NOD) mice and wild-type (WT) mice in the same strain background, an infection was mimicked by toll-like receptor 9 (TLR9) activation through CpG1826-injection. In vivo inactivation of IL-10 was performed to enhance pregnancy loss. Regulatory T cells induced by FTY720 in vitro from splenic CD4+CD25-Foxp3- cells (iTreg cells) were transferred to improve pregnancy outcomes in NOD mice.


RESULTS
Embryo-resorption and preterm birth were readily induced by CpG1826 in NOD mice, but not in WT mice. However, inactivation of IL-10 using neutralizing antibody injections enhanced pregnancy loss in WT mice exposed to CpG, while adoptive transfer of iTreg cells increased decidual Foxp3+ Treg cells and IL-10+ cell number and rescued pregnancy.


CONCLUSIONS
NOD mice are prone to abortion and preterm birth. This can be attributed to lacking Treg cells and insufficient IL-10 expression. Adoptive transfer of iTreg cells can rescue CpG-mediated pregnancy failure.
International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Yi
Y
Lin
International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Xiaorui
X
Liu
Medical Sciences, Washington State University Spokane, Spokane, Washington, United States of America.
Bin
B
Shan
Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China.
Ji
J
Wu
Department of Pediatrics, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
Surendra
S
Sharma
Department of Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China.
Yun
Y
Sun
D000022:Abortion, Spontaneous / Q000139:chemically induced* / Q000276:immunology / Q000517:prevention & control*; D019264:Adoptive Transfer; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000378:metabolism; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000009:adverse effects*; D010641:Phenotype; D011247:Pregnancy; D011256:Pregnancy Outcome; D047928:Premature Birth / Q000139:chemically induced* / Q000276:immunology / Q000517:prevention & control*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D009838:Oligodeoxyribonucleotides; D016753:Interleukin-10