Abstract
Regulatory T cells (Tregs) are critical immunomodulators during early pregnancy by preventing maternal T-cell activation against fetal cells. However, how populations of maternal Tregs vary during and after pregnancy in humans is still unclear. Therefore, we investigated Treg subsets in the peripheral blood of pregnant women from late pregnancy through the postpartum period. To accomplish this, the following circulating Treg subsets were analyzed in 43 healthy pregnant women and 35 nonpregnant women by flow cytometry during the third trimester, on the day of delivery, and postpartum: CD4DimCD25Hi, CD4+CD25HiFoxp3+, and CD4+CD25HiCD127–/dim. Additionally, the expression levels of the transcription factor Foxp3 in CD4 imCD25Hi Treg were analyzed. We have found that CD4DimCD25Hi Treg subset significantly decreased in the pregnant women on the day of delivery relative to the third trimester (P <.05), and that all Treg subsets significantly increased postpartum compared to the third trimester and the day of delivery (P <.05). Moreover, the Foxp3 expression ratios within the CD4DimCD25Hi Treg subset decreased during pregnancy and until delivery compared to those measured in the nonpregnant women and significantly increased postpartum compared to the third trimester and the day of delivery (P <.05). Thus, despite their established role in offering immunoprotection to the fetus in early pregnancy, the number of circulating Tregs also varies from late pregnancy to the postpartum period. Our results offer an explanation for the possible effects of pregnancy on the clinical outcomes of some autoimmune diseases during the postpartum period.
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Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immuno-logic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155(3):1151–1164.
Aluvihare VR, Kallikourdis M, Betz AG. Regulatory T cells med-iate maternal tolerance to the fetus. Nat Immunol. 2004;5(3):266–271.
Xiong YH, Yuan Z, He L. Effects of estrogen on CD4(+) CD25(+) regulatory T cell in peripheral blood during pregnancy. Asian Pac J Trop Med. 2013;6(9):748–752.
Heikkinen J, Mottonen M, Alanen A, Lassila O. Phenotypic char-acterization of regulatory T cells in the human decidua. Clin Exp Immunol. 2004;136(2):373–378.
Zenclussen AC, Gerlof K, Zenclussen ML, et al. Abnormal T-cell reactivity against paternal antigens in spontaneous abortion: adoptive transfer of pregnancy-induced CD4+CD25+ T regula-tory cells prevents fetal rejection in a murine abortion model. Am J Pathol. 2005;166(3):811–822.
Sasaki Y, Darmochwal-Kolarz D, Suzuki D, et al. Proportion of peripheral blood and decidual CD4(+) CD25(bright) regulatory T cells in pre-eclampsia. Clin Exp Immunol. 2007;149(1):139–145.
Darmochwal-Kolarz D, Saito S, Rolinski J, et al. Activated T lymphocytes in pre-eclampsia. Am J Reprod Immunol. 2007; 58(1):39–45.
Nakashima A, Shima T, Inada K, Ito M, Saito S. The balance of the immune system between T cells and NK cells in miscarriage. Am J Reprod Immunol. 2012;67(4):304–310.
Koucky M, Malickova K, Cindrova-Davies T, et al. Low levels of circulating T-regulatory lymphocytes and short cervical length are associated with preterm labor. J Reprod Immunol. 2014;106:110–117.
Xiong H, Zhou C, Qi G. Proportional changes of CD4+ CD25+Foxp3+ regulatory T cells in maternal peripheral blood during pregnancy and labor at term and preterm. Clin Invest Med. 2010;33(6):E422.
Roncador G, Brown PJ, Maestre L, et al. Analysis of FOXP3 protein expression in human CD4+CD25+ regulatory T cells at the single-cell level. Eur J Immunol. 2005;35(6):1681–1691.
Finak G, Langweiler M, Jaimes M, et al. Standardizing flow cytometry immunophenotyping analysis from the Human Immu-noPhenotyping Consortium. Sei Rep. 2016;6:20686.
Liu W, Putnam AL, Xu-Yu Z, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006;203(7):1701–1711.
Seddiki N, Santner-Nanan B, Martinson J, et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med. 2006;203(7):1693–1700.
Santner-Nanan B, Peek MJ, Khanam R, et al. Systemic increase in the ratio between Foxp3+ and IL-17-producing CD4+ T cells in healthy pregnancy but not in preeclampsia. J Immunol. 2009;183(11):7023–7030.
Saito S, Nakashima A, Shima T, Ito M. Thl/Th2/Thl7 and reg-ulatory T-cell paradigm in pregnancy. Am J Reprod Immunol. 2010;63(6):601–610.
Tilburgs T, Roelen DL, van der Mast BJ, et al. Differential dis-tribution of CD4(+)CD25(bright) and CD8(+)CD28(-) T-cells in decidua and maternal blood during human pregnancy. Placenta. 2006;27(suppl A):S47–S53.
Kisielewicz A, Schaier M, Schmitt E, et al. A distinct subset of HLA-DR+-regulatory T cells is involved in the induction of pre-term labor during pregnancy and in the induction of organ rejection after transplantation. Clin Immunol. 2010;137(2):209–220.
Somerset DA, Zheng Y, Kilby MD, Sansom DM, Drayson MT. Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset. Immunology. 2004;112(1):38–43.
Steinborn A, Haensch GM, Mahnke K, et al. Distinct subsets of regulatory T cells during pregnancy: is the imbalance of these subsets involved in the pathogenesis of preeclampsia? Clin Immunol. 2008;129(3):401–412.
Sasaki Y, Sakai M, Miyazaki S, Higuma S, Shiozaki A, Saito S. Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases. Mol Hum Reprod. 2004;10(5):347–353.
Seol HJ, Oh MJ, Lim JE, Jung NH, Yoon SY, Kim HJ. The role of CD4+CD25bright regulatory T cells in the maintenance of preg-nancy, premature rupture of membranes, and labor. Yonsei Med J. 2008;49(3):366–371.
Mjosberg J, Svensson J, Johansson E, et al. Systemic reduction of functionally suppressive CD4dimCD25highFoxp3+ Tregs in human second trimester pregnancy is induced by progesterone and 17beta-estradiol. J Immunol. 2009;183(1):759–769.
Areia A, Vale-Pereira S, Alves V, et al. Can membrane proges-terone receptor alpha on T regulatory cells explain the ensuing human labour? J Reprod Immunol. 2015;113:22–26.
Wegienka G, Havstad S, Bobbitt KR, et al. Within-woman change in regulatory T cells from pregnancy to the postpartum period. J Reprod Immunol. 2011;88(1):58–65.
Auerbach L, Hafner T, Huber JC, Panzer S. Influence of low-dose oral contraception on peripheral blood lymphocyte subsets at particular phases of the hormonal cycle. Fertil Steril. 2002;78(1):83–89.
Hulspas R, O’Gorman MR, Wood BL, Gratama JW, Sutherland DR. Considerations for the control of background fluorescence in clinical flow cytometry. Cytometry B Clin Cytom. 2009;76(6):355–364.
Keeney M, Gratama JW, Chin-Yee IH, Sutherland DR. Isotype controls in the analysis of lymphocytes and CD34+ stem and progenitor cells by flow cytometry-time to let go! Cytometry. 1998;34(6):280–283.
Dendrou CA, Fung E, Esposito L, Todd JA, Wicker LS, Plagnol V. Fluorescence intensity normalisation: correcting for time effects in large-scale flow cytometric analysis. Adv Bioinfor-matics. 2009;2009:476106.
Benjamini Y, Yekutieli D. The control of the false discovery rate in multiple testing under dependency. Ann Stat. 2001;29(4):1165–1188.
Loewendorf AI, Nguyen TA, Yesayan MN, Kahn DA. Normal human pregnancy results in maternal immune activation in the periphery and at the uteroplacental interface. PLoS One. 2014;9(5):e96723.
Galazka K, Wicherek L, Pitynski K, et al. Changes in the sub-population of CD25+ CD4+ and FOXP3+ regulatory T cells in decidua with respect to the progression of labor at term and the lack of analogical changes in the subpopulation of suppressive B7-H4 macrophages—a preliminary report. Am J Reprod Immunol. 2009;61(2):136–146.
Areia A, Vale-Pereira S, Alves V, Rodrigues-Santos P, Moura P, Mota-Pinto A. Membrane progesterone receptors in human reg-ulatory T cells: a reality in pregnancy. BJOG. 2015;122(11):1544–1550.
Lima J, Martins C, Leandro MJ, et al. Characterization of B cells in healthy pregnant women from late pregnancy to post-partum: a prospective observational study. BMC Pregnancy Childbirth. 2016;16(1):1–13.
Flores-Borja F, Bosma A, Ng D, et al. CD19+CD24hiCD38hi B cells maintain regulatory T cells while limiting TH1 and TH17 differentiation. Sei Transi Med. 2013;5(173):173ra23.
Kessel A, Haj T, Peri R, et al. Human CD19(+)CD25(high) B regulatory cells suppress proliferation of CD4(+) T cells and enhance Foxp3 and CTLA-4 expression in T-regulatory cells. Autoimmun Rev. 2012;11(9):670–677.
Shinoda R, Watanabe M, Nakamura Y, Maruoka H, Kimura Y, Iwatani Y. Physiological changes of Fas expression in peripheral lymphocyte subsets during the menstrual cycle. J Reprod Immunol. 2003;60(2):159–168.
Arruvito L, Sanz M, Banham AH, Fainboim L. Expansion of CD4+CD25+and FOXP3+ regulatory T cells during the follicular phase of the menstrual cycle: implications for human reproduction. J Immunol. 2007;178(4):2572–2578.
Morgan ME, van Bilsen JH, Bakker AM, et al. Expression of FOXP3 mRNA is not confined to CD4+CD25+ T regulatory cells in humans. Hum Immunol. 2005;66(1):13–20.
Habibagahi M, Habibagahi Z, Jaberipour M, Aghdashi A. Quan-tification of regulatory T cells in peripheral blood of patients with systemic lupus erythematosus. Rheumatol Int. 2011;31(9):1219–1225.
Perricone C, de Carolis C, Perricone R. Pregnancy and autoimmunity: a common problem. Best Pract Res Clin Rheumatol. 2012;26(1):47–60.
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Lima, J., Martins, C., Nunes, G. et al. Regulatory T Cells Show Dynamic Behavior During Late Pregnancy, Delivery, and the Postpartum Period. Reprod. Sci. 24, 1025–1032 (2017). https://doi.org/10.1177/1933719116676395
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DOI: https://doi.org/10.1177/1933719116676395