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Human Chorionic Gonadotropin Attracts Regulatory T Cells into the Fetal-Maternal Interface during Early Human Pregnancy¹

Anne Schumacher^*, Nadja Brachwitz^*, Sindy Sohr, Kurt Engeland, Stefanie Langwisch^*, Maria Dolaptchieva, Tobias Alexander, Andrei Taran^*,¶, Sara Fill Malfertheiner^*,¶, Serban-Dan Costa^¶, Gerolf Zimmermann, Cindy Nitschke^||, Hans-Dieter Volk, Henry Alexander, Matthias Gunzer^|| and Ana Claudia Zenclussen^2,*

^* Department of Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany; Department of Obstetrics and Gynecology, University of Leipzig, Leipzig, Germany; Institute of Medical Immunology and Department of Rheumatology and Clinical Immunology, Charité, Universitätsmedizin, Berlin, Germany; and ^¶ Department of Obstetrics and Gynecology and ^|| Institute of Molecular Immunology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany

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-β 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Deutsche Forschungsgemeinschaft (Ze526/04-2) to A.C.Z. and the Interdisciplinary Center for Clinical Research (IZKF) Leipzig (Projekt D02) to K.E.

² Address correspondence and reprint requests to Dr. Ana Claudia Zenclussen, Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke-University Magdeburg, Gerhart-Hauptmann-Strasse 35, 39108 Magdeburg, Germany. E-mail address: ana.zenclussen{at}med.ovgu.de

³ Abbreviations used in this paper: Treg, regulatory T cells; hCG, human chorionic gonadotropin; HCT116, human colon carcinoma 116; RT, room temperature; Nrp-1, neuropilin-1; LH/CG, luteinizing hormone/chorionic gonadotropin; IVF, in vitro fertilization.

⁴ The online version of this article contains supplemental material.