Human chorionic gonadotropin attracts regulatory T cells into the fetal-maternal interface during early human pregnancy.
Regulatory T cells (Treg) expand during pregnancy and are present at the fetal-maternal interface at very early stages in pregnancy. The migration mechanisms of Treg to the pregnant uterus are still unclear. Human chorionic gonadotropin (hCG) is secreted by the blastocyst immediately after fertilization and has chemoattractant properties. Therefore, we sought to analyze whether hCG secreted by early trophoblasts attracts Treg to the uterus and hence contributes to maternal tolerance toward the fetus. Decidua and placenta tissue samples from patients having spontaneous abortions or ectopic pregnancies were employed to evaluate Treg and hCG levels. Age-matched samples from normal pregnant women served as controls. We further performed in vitro studies with primary first trimester trophoblast cells and a choriocarcinoma cell line (JEG-3) aiming to evaluate the ability of secreted hCG to attract Treg. Patients having miscarriages or ectopic pregnancy presented significantly decreased hCG mRNA and protein levels associated with decreased Foxp3, neuropilin-1, IL-10, and TGF-beta mRNA levels as compared with normal pregnant women. Using migration assays we demonstrated that Treg were attracted by hCG-producing trophoblasts or choriocarcinoma cells. Treg migration toward cells transfected with hCG expression vectors confirmed the chemoattractant ability of hCG. Our data clearly show that hCG produced by trophoblasts attracts Treg to the fetal-maternal interface. High hCG levels at very early pregnancy stages ensure Treg to migrate to the site of contact between paternal Ags and maternal immune cells and to orchestrate immune tolerance toward the fetus.
Schumacher
Anne
A
Department of Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
Brachwitz
Nadja
N
Sohr
Sindy
S
Engeland
Kurt
K
Langwisch
Stefanie
S
Dolaptchieva
Maria
M
Alexander
Tobias
T
Taran
Andrei
A
Malfertheiner
Sara Fill
SF
Costa
Serban-Dan
SD
Zimmermann
Gerolf
G
Nitschke
Cindy
C
Volk
Hans-Dieter
HD
Alexander
Henry
H
Gunzer
Matthias
M
Zenclussen
Ana Claudia
AC
D000022:Abortion, Spontaneous / Q000276:immunology / Q000378:metabolism; D000328:Adult; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018920:Coculture Techniques; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D008431:Maternal-Fetal Exchange / Q000276:immunology*; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000276:immunology; D011262:Pregnancy Trimester, Second / Q000276:immunology; D011271:Pregnancy, Ectopic / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
D006063:Chorionic Gonadotropin