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Evidence for a Selective Migration of Fetus-Specific CD4⁺CD25^bright Regulatory T Cells from the Peripheral Blood to the Decidua in Human Pregnancy

Tamara Tilburgs^1,*,, Dave L. Roelen^*, Barbara J. van der Mast, Godelieve M. de Groot-Swings, Carin Kleijburg, Sicco A. Scherjon and Frans H. Claas^*

^* Department of Immunohematology and Blood Transfusion and Department of Obstetrics, Leiden University Medical Centre, Leiden, The Netherlands

During pregnancy, the maternal immune system has to tolerate the persistence of fetal alloantigens. Many mechanisms contribute to the prevention of a destructive immune response mediated by maternal alloreactive lymphocytes directed against the allogeneic fetus. Murine studies suggest that CD4⁺CD25⁺ T cells provide mechanisms of specific immune tolerance to fetal alloantigens during pregnancy. Previous studies by our group demonstrate that a significantly higher percentage of activated T cells and CD4⁺CD25^bright T cells are present in decidual tissue in comparison with maternal peripheral blood in human pregnancy. In this study, we examined the phenotypic and functional properties of CD4⁺CD25^bright T cells derived from maternal peripheral blood and decidual tissue. Depletion of CD4⁺CD25^bright T cells from maternal peripheral blood demonstrates regulation to third party umbilical cord blood cells comparable to nonpregnant controls, whereas the suppressive capacity to umbilical cord blood cells of her own child is absent. Furthermore, maternal peripheral blood shows a reduced percentage of CD4⁺CD25^brightFOXP3⁺ and CD4⁺CD25^brightHLA-DR⁺ cells compared with peripheral blood of nonpregnant controls. In contrast, decidual lymphocyte isolates contain high percentages of CD4⁺CD25^bright T cells with a regulatory phenotype that is able to down-regulate fetus-specific and fetus-nonspecific immune responses. These data suggest a preferential recruitment of fetus-specific regulatory T cells from maternal peripheral blood to the fetal-maternal interface, where they may contribute to the local regulation of fetus-specific responses.

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 Address correspondence and reprint requests to Dr. Tamara Tilburgs, Leiden University Medical Centre, Department of Immunohematology and Blood Transfusion E3Q, PO Box 9600, 2300 RC Leiden, The Netherlands. E-mail address: T.Tilburgs{at}LUMC.nl

² Abbreviations used in this paper: Treg, T regulatory; cPBL, control PBL; d.basalis, decidua basalis; d.parietalis, decidua parietalis; mPBL, maternal PBL; S.I., suppression index; UCB, umbilical cord blood.

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