Altered Frequencies of CD4+ CD25+ Foxp3+ and CD8+ CD25+ Foxp3+ Regulatory T Cells in Pre-eclampsia
Regulatory T cells are of utmost importance for tolerating the fetus. In some pregnancy complications such as pre-eclampsia, the frequency of CD4+CD25+Foxp3+ regulatory T cells is altered, but there is no consistency regarding the results. Besides, little is known about the frequency of CD8+CD25+Foxp3+ Treg cells in pregnancy complications. Therefore, we aimed to investigate the frequency of both CD4+ and CD8+ regulatory T cells in the peripheral blood of women afflicted by preeclampsia. Ten non-pregnant, ten healthy pregnant, and ten preeclamptic women participated in this study. Four colors flow cytometry method was used to identify the frequency of the CD4+ and CD8+ regulatory T cells in the peripheral blood. Results indicated that the frequencies of CD4+CD25+Foxp3+ and CD8+CD25+Foxp3+ cells were significantly lower in preeclamptic women compared to healthy pregnant and non-pregnant ones (p<0.05). A positive correlation was also observed between CD4+ and CD8+ regulatory T cells (R= 0.532, p=0.002). Moreover, CD4+ regulatory T cells negatively correlated with systolic and diastolic blood pressures (R=-0.760 and -0.753, respectively; p<0.001). CD8+ regulatory T cells also had a negative correlation with systolic (R=-0.503, p=0.001) and diastolic (R=-0.590, p=0.005) blood pressures. In conclusion, a reduction in the frequencies of both CD4+ CD25+ Foxp3+ and CD8+CD25+Foxp3+ regulatory T cells might be important in the pathogenesis of pre-eclampsia.
1. PrabhuDas M, Bonney E, Caron K, Dey S, Erlebacher A, Fazleabas A, et al. Immune mechanisms at the maternal-fetal interface: perspectives and challenges. Nature immunology. 2015;16(4):328-34.
2. Warning JC, McCracken SA, Morris JM. A balancing act: mechanisms by which the fetus avoids rejection by the maternal immune system. Reproduction (Cambridge, England). 2011;141(6):715-24.
3. La Rocca C, Carbone F, Longobardi S, Matarese G. The immunology of pregnancy: regulatory T cells control maternal immune tolerance toward the fetus. Immunology letters. 2014;162(1 Pt A):41-8.
4. Warrington JP, George EM, Palei AC, Spradley FT, Granger JP. Recent advances in the understanding of the pathophysiology of preeclampsia. Hypertension (Dallas, Tex : 1979). 2013;62(4):666-73.
5. Laresgoiti-Servitje E. A leading role for the immune system in the pathophysiology of preeclampsia. Journal of leukocyte biology. 2013;94(2):247-57.
6. Cerdeira AS, Kopcow HD, Karumanchi SA. Regulatory T Cells in Preeclampsia: Some Answers, More Questions? The American Journal of Pathology. 2012;181(6):1900-2.
7. Ruocco MG, Chaouat G, Florez L, Bensussan A, Klatzmann D. Regulatory T-Cells in Pregnancy: Historical Perspective, State of the Art, and Burning Questions. Frontiers in immunology. 2014;5.
8. Peterson RA. Regulatory T-cells: diverse phenotypes integral to immune homeostasis and suppression. Toxicologic pathology. 2012;40(2):186-204.
9. Jiang TT, Chaturvedi V, Ertelt JM, Kinder JM, Clark DR, Valent AM, et al. Regulatory T cells: new keys for further unlocking the enigma of fetal tolerance and pregnancy complications. Journal of immunology (Baltimore, Md : 1950). 2014;192(11):4949-56.
10. Craenmehr MH, Heidt S, Eikmans M, Claas FH. What is wrong with the regulatory T cells and foetomaternal tolerance in women with recurrent miscarriages? Hla. 2016;87(2):69-78.
11. Gomez-Lopez N, StLouis D, Lehr MA, Sanchez-Rodriguez EN, Arenas-Hernandez M. Immune cells in term and preterm labor. Cellular & molecular immunology. 2014;11(6):571-81.
12. Schober L, Radnai D, Schmitt E, Mahnke K, Sohn C, Steinborn A. Term and preterm labor: decreased suppressive activity and changes in composition of the regulatory T-cell pool. Immunology and cell biology. 2012;90(10):935-44.
13. Prins JR, Boelens HM, Heimweg J, Van der Heide S, Dubois AE, Van Oosterhout AJ, et al. Preeclampsia is associated with lower percentages of regulatory T cells in maternal blood. Hypertension in pregnancy. 2009;28(3):300-11.
14. Rahimzadeh M, Norouzian M, Arabpour F, Naderi N. Regulatory T-cells and preeclampsia: an overview of literature. Expert review of clinical immunology. 2016;12(2):209-27.
15. Paeschke S, Chen F, Horn N, Fotopoulou C, Zambon-Bertoja A, Sollwedel A, et al. Pre-eclampsia is not associated with changes in the levels of regulatory T cells in peripheral blood. American journal of reproductive immunology (New York, NY : 1989). 2005;54(6):384-9.
16. Churlaud G, Pitoiset F, Jebbawi F, Lorenzon R, Bellier B, Rosenzwajg M, et al. Human and Mouse CD8(+)CD25(+)FOXP3(+) Regulatory T Cells at Steady State and during Interleukin-2 Therapy. Frontiers in immunology. 2015;6:171.
17. Chaput N, Louafi S, Bardier A, Charlotte F, Vaillant JC, Menegaux F, et al. Identification of CD8+CD25+Foxp3+ suppressive T cells in colorectal cancer tissue. Gut. 2009;58(4):520-9.
18. Robb RJ, Lineburg KE, Kuns RD, Wilson YA, Raffelt NC, Olver SD, et al. Identification and expansion of highly suppressive CD8(+)FoxP3(+) regulatory T cells after experimental allogeneic bone marrow transplantation. Blood. 2012;119(24):5898-908.
19. Ligocki AJ, Niederkorn JY. Advances on Non-CD4 + Foxp3+ T Regulatory Cells: CD8+, Type 1, and Double Negative T Regulatory Cells in Organ Transplantation. Transplantation. 2015;99(8):1553-9.
20. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstetrics and gynecology. 2013;122(5):1122-31.
21. Toldi G, Saito S, Shima T, Halmos A, Veresh Z, Vasarhelyi B, et al. The frequency of peripheral blood CD4+ CD25high FoxP3+ and CD4+ CD25- FoxP3+ regulatory T cells in normal pregnancy and pre-eclampsia. American journal of reproductive immunology (New York, NY : 1989). 2012;68(2):175-80.
22. Toldi G, Svec P, Vasarhelyi B, Meszaros G, Rigo J, Tulassay T, et al. Decreased number of FoxP3+ regulatory T cells in preeclampsia. Acta Obstet Gynecol Scand. 2008;87(11):1229-33.
23. Hu D, Chen YAN, Zhang W, Wang H, Wang Z, Dong M. Alteration of peripheral CD4+CD25+ regulatory T lymphocytes in pregnancy and pre-eclampsia. Acta Obstetricia et Gynecologica Scandinavica. 2008;87(2):190-4.
24. Nagayama S, Ohkuchi A, Shirasuna K, Takahashi K, Suzuki H, Hirashima C, et al. The Frequency of Peripheral Blood CD4+FoxP3+ Regulatory T Cells in Women With Pre-eclampsia and Those With High-risk Factors for Pre-eclampsia. Hypertension in pregnancy. 2015;34(4):443-55.
25. Steinborn A, Haensch GM, Mahnke K, Schmitt E, Toermer A, Meuer S, et al. Distinct subsets of regulatory T cells during pregnancy: is the imbalance of these subsets involved in the pathogenesis of preeclampsia? Clinical immunology (Orlando, Fla). 2008;129(3):401-12.
26. Polese B, Gridelet V, Araklioti E, Martens H, Perrier d'Hauterive S, Geenen V. The Endocrine Milieu and CD4 T-Lymphocyte Polarization during Pregnancy. Frontiers in endocrinology. 2014;5:106.
27. Walecki M, Eisel F, Klug J, Baal N, Paradowska-Dogan A, Wahle E, et al. Androgen receptor modulates Foxp3 expression in CD4+CD25+Foxp3+ regulatory T-cells. Molecular biology of the cell. 2015;26(15):2845-57.
28. Ruocco MG, Chaouat G, Florez L, Bensussan A, Klatzmann D. Regulatory T-cells in pregnancy: historical perspective, state of the art, and burning questions. Frontiers in immunology. 2014;5:389.
29. Polanczyk MJ, Hopke C, Vandenbark AA, Offner H. Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1 costimulatory pathway. Journal of neuroscience research. 2006;84(2):370-8.
30. Yu J, Qian L, Wu F, Li M, Chen W, Wang H. Decreased frequency of peripheral blood CD8+CD25+FoxP3+regulatory T cells correlates with IL-33 levels in pre-eclampsia. Hypertension in pregnancy. 2017;36(2):217-25.
31. Emoto T, Sasaki N, Yamashita T, Kasahara K, Yodoi K, Sasaki Y, et al. Regulatory/effector T-cell ratio is reduced in coronary artery disease. Circulation journal : official journal of the Japanese Circulation Society. 2014;78(12):2935-41.
32. Sada Y, Dohi Y. Non-suppressive regulatory T cell subset expansion in pulmonary arterial hypertension. 2016;31(8):1319-26.