Lymphocyte Activation in the Development of Immune Tolerance in Women with Recurrent Pregnancy Loss

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L. V. Krechetova¹, L. V. Vanko¹, V. V. Vtorushina¹, M. A. Nikolaeva¹, E. V. Inviyaeva^1,a*, and N. K. Tetruashvili¹

¹National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Healthcare of the Russian Federation, 117997 Moscow, Russia

^* To whom correspondence should be addressed.

Received November 8, 2019; Revised March 20, 2020; Accepted March 20, 2020

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Association between lymphocyte activation and formation of immune tolerance, as well as pregnancy outcome, in the case of immunocytotherapy (ICT) was studied in women with idiopathic recurrent pregnancy loss (IRPL). The content and phenotypic characteristics of activated T lymphocytes and NK cells were investigated in the peripheral blood of IRPL patients with different pregnancy outcomes (pregnancy prolongation to the full term and habitual miscarriage). The fraction of activated cells in the subpopulation of cytotoxic T lymphocytes (CD3⁺CD8⁺/CD3⁺CD8⁺CD69⁺) before ICT was significantly lower in women who lost the pregnancy. After ICT, the fraction of these cells during weeks 5-6 of pregnancy in woman with miscarriage was higher than in women with pregnancy prolonged to the full-term. Excessive content of activated cytotoxic lymphocytes can be a mechanism underlying impaired maternal immunotolerance to fetal alloantigens, which is a leading factor of early pregnancy loss. The obtained data confirm the involvement of activated Th17 cells and FOXP3⁺ Treg cells in the formation of tolerance to paternal antigens of the fetus. Comparison of the decrease in the fraction of CD4⁺CD25^highRORγt⁺ lymphocytes at the early gestation period (5-6 weeks) and significant upregulation of the IL-17 production by in vitro stimulated whole blood cells in women with miscarriage with the same parameters in women with prolonged pregnancy suggested an imbalance between pro-inflammatory Th17 cells and Treg cells. No such imbalance in the content effector T lymphocytes was observed in women with the full-term pregnancy. Taken together, our data indicate an important role of gestational activation of lymphocytes in the formation of maternal immune response to fetal alloantigens necessary for the prolongation of pregnancy.

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KEY WORDS: immunotolerance, recurrent pregnancy loss, immunocytotherapy, CD69 expression, T lymphocytes, NK cells

DOI: 10.1134/S0006297920050077

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