title: Human chorionic gonadotropin attracts regulatory T cells into the fetal-maternal interface during early human pregnancy.
abstract: 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.
authors.affiliation: Department of Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Schumacher
authors.forename: Nadja
authors.initials: N
authors.lastname: Brachwitz
authors.forename: Sindy
authors.initials: S
authors.lastname: Sohr
authors.forename: Kurt
authors.initials: K
authors.lastname: Engeland
authors.forename: Stefanie
authors.initials: S
authors.lastname: Langwisch
authors.forename: Maria
authors.initials: M
authors.lastname: Dolaptchieva
authors.forename: Tobias
authors.initials: T
authors.lastname: Alexander
authors.forename: Andrei
authors.initials: A
authors.lastname: Taran
authors.forename: Sara Fill
authors.initials: SF
authors.lastname: Malfertheiner
authors.forename: Serban-Dan
authors.initials: SD
authors.lastname: Costa
authors.forename: Gerolf
authors.initials: G
authors.lastname: Zimmermann
authors.forename: Cindy
authors.initials: C
authors.lastname: Nitschke
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
authors.forename: Henry
authors.initials: H
authors.lastname: Alexander
authors.forename: Matthias
authors.initials: M
authors.lastname: Gunzer
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Zenclussen
mesh_terms: 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*
chemical_list: D006063:Chorionic Gonadotropin