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Systemic Reduction of Functionally Suppressive CD4^dimCD25^highFoxp3⁺ Tregs in Human Second Trimester Pregnancy Is Induced by Progesterone and 17β-Estradiol¹

Jenny Mjösberg^2,*, Judit Svensson^*, Emma Johansson^*, Lotta Hellström^*, Rosaura Casas, Maria C. Jenmalm, Roland Boij^¶, Leif Matthiesen^||, Jan-Ingvar Jönsson, Göran Berg and Jan Ernerudh^*

^* Division of Clinical Immunology, Unit for Autoimmunity and Immune Regulation, Division of Pediatrics, Division of Cell Biology, and Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; ^¶ Department of Obstetrics and Gynecology, Ryhov Hospital, Jönköping, Sweden; and ^|| Department of Obstetrics and Gynecology, Helsingborg Hospital, Helsingborg, Sweden

CD4⁺CD25^high regulatory T cells (Tregs) are implicated in the maintenance of murine pregnancy. However, reports regarding circulating Treg frequencies in human pregnancy are inconsistent, and the functionality and phenotype of these cells in pregnancy have not been clarified. The aim of this study was to determine the frequency, phenotype, and function of circulating Tregs in the second trimester of human pregnancy and the influence of progesterone and 17β-estradiol on Treg phenotype and frequency. Based on expressions of Foxp3, CD127, and HLA-DR as determined by multicolor flow cytometry, we defined a proper CD4^dimCD25^high Treg population and showed, in contrast to most previous reports, that this population was reduced in second trimester of pregnancy. Unexpectedly, Foxp3 expression was decreased in the Treg, as well as in the CD4⁺ population. These changes could be replicated in an in vitro system resembling the pregnancy hormonal milieu, where 17β-estradiol, and in particular progesterone, induced, in line with the pregnancy situation, a reduction of CD4^dimCD25^highFoxp3⁺ cells in PBMC from nonpregnant women. By coculturing FACS-sorted Tregs and autologous CD4⁺CD25^– responder cells, we showed that Tregs from pregnant women still displayed the same suppressive capacity as nonpregnant women in terms of suppressing IL-2, TNF-, and IFN- secretion from responder cells while efficiently producing IL-4 and IL-10. Our findings support the view of hormones, particularly progesterone, as critical regulators of Tregs in pregnancy. Furthermore, we suggest that in the light of the results of this study, early data on circulating Treg frequencies in pregnancy need reevaluation.

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 Swedish Research Council Grant 2007-15809-48800-58, Health Research Council in the South East of Sweden Grant FORSS-8805, and Östergötland County Council Grant LIO-8255.

² Address correspondence and reprint requests to MSc. Jenny Mjösberg, Unit for Autoimmunity and Immune Regulation, Division of Clinical Immunology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, 581 85 Linköping, Sweden. E-mail address: jenny.mjosberg{at}liu.se

³ Abbreviations used in this paper: Treg, regulatory T cell; Foxp3, Forkhead box P3; TCM, T cell culture medium.