To date, pregnancy is an immunological paradox. The semi-allogenic fetus must be accepted by the maternal immune system, while defense against pathogens and immune surveillance cannot be compromised. Gamma/delta T cells are believed to play an important role in this immunological puzzle. In this study, we analyzed peripheral blood CD56+ γδT cells from pregnant women (1st, 2nd, and 3rd trimester) and non-pregnant women by multicolor flow cytometry. Interestingly, γδT cells represent almost half of CD3+/CD56+ cells. Among γδT cells, the CD56+ population expands in the 2nd and 3rd trimester. CD56+ γδT cells maintained a predominantly CD4–/CD8– or CD8+ phenotype, while CD56– γδT cells were in similar rates CD4–/CD8– or CD4+ during pregnancy. Investigation of the lysosomal degranulation marker CD107a revealed a preserved elevated rate of potentially cytotoxic CD56+ γδT cells in pregnancy, while their cytotoxic strength was reduced. Furthermore, CD56+ γδT cells continuously showed a higher prevalence of PD-1 expression. CD56+ γδT cells’ rate of PD-1 increased in the 1st trimester and decreased hereafter back to normal level. We correlated the cytotoxic potential and the expression of the inhibitory immune checkpoint PD-1 and were able to demonstrate that highly cytotoxic cells within this CD56+ γδT population tend to express PD-1, which might allow the inhibition of these cells after binding its ligand in the placenta. These findings should support the understanding of the complex processes, which ensure the maintenance of pregnancy.

Pregnancy is an immunological enigma where paternal antigens are present at the fetomaternal interface. What regulates the local immunotolerance, which is necessary to prevent rejection of the conceptus, is still under strong investigation. Gamma/delta T cells are believed to play a role in the local regulation of this immunotolerance towards the semiallogenic fetus. Gamma/delta T cells from the uterus and spleen of pregnant and nonpregnant mice were analyzed by flow cytometry. We confirmed that the rate of γδT cells in the decidua increases during murine pregnancy and half of decidual γδT cells are CD4+. Furthermore, we found a unique association of CD4 or CD8 coreceptor expression with their γδTCR intensity, where in all investigated groups CD4- or CD8-positive γδT cells seemed principally to be γδTCRdim. In addition, compared to peripheral γδT lymphocytes, a greater proportion of decidual γδT cells expressed the cytotoxic marker CD107a and markers of Th1 or Th2 polarization (TIM-3, TIM-1), where decidual γδTCRbright cells were characterized by high TIM-3 and TIM-1 receptor expression. On the other hand, no difference in the expression of CD160, a receptor with dual function affecting cytotoxicity and T cell inhibition, was detected. Within lymphocytes expressing CD107a, TIM-1, or CD160, the rate of γδT cells was significantly higher in the decidua. According to our results, cytotoxic potential of decidual γδTCRbright cells could be regulated by TIM-3 ligation, while the TIM-1 receptor seems to be able to influence the Th1-Th2 balance at the fetomaternal interface. These mechanisms could play a part in the active maternal immunotolerance towards the fetus, allowing an efficient protection against pathogens during healthy murine pregnancy.

The expansion of CD4-expressing CD160 decidual lymphocytes is a new observation suggesting a potential regulatory role of T-cell function during mouse pregnancy. The altered immunological character of CD160 lymphocytes could play a role in the maintenance of murine pregnancy.

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Anti-thyroid antibody (ATA) positivity affects 1 out of 9 women in childbearing age and presents a significant risk for infertility. Emerging evidence indicates that alterations in the B cell receptor induced calcium (Ca2+) signaling could be key in the development of autoimmunity. We aimed to investigate the Ca2+ flux response of B lymphocyte subsets to BCR stimulation in Hashimoto’s thyroiditis and related infertility. We collected peripheral blood samples from ATA+, infertile, euthyroid patients (HIE), hypothyroid, ATA+ patients before (H1) and after levothyroxine treatment (H2), and age-matched healthy controls (HC). All B cell subsets of ATA+, infertile, euthyroid patients showed elevated basal Ca2+ level and hyper-responsivity to BCR ligation compared to the other groups, which could reflect altered systemic immune function. The Ca2+ flux of hypothyroid patients was similar to healthy controls. The levothyroxine-treated patients had decreased prevalence of CD25+ B cells and lower basal Ca2+ level compared to pre-treatment. Our results support the role of altered Ca2+ flux of B cells in the early phase of thyroid autoimmunity and infertility.