The importance of the PD-1/PD-L1 pathway at the maternal-fetal interface

Abstract

Background Our goal with this study was to investigate the contribution of PD-1/PD-L1 immune-checkpoint pathway to maternal immunotolerance mechanisms. Methods Thirteen healthy pregnant women and 10 non-pregnant controls were involved in this project. PBMCs and DICs were isolated from peripheral blood and from decidual tissues. After the characterization of different immune cell subsets, we used fluorochrome-conjugated monoclonal antibodies to measure the expression level of PD-1, PD-L1, NKG2D, and CD107a molecules by flow cytometry. Results We measured significant alternations in the proportion of decidual immune cell subsets compared to the periphery. Elevated PD-1 expression by decidual CD8+ T, CD4+ T, and NKT-like cells were also detected accompanied by the increased PD-L1 expression by decidual CD4+ T, Treg, NKT-like and CD56 + NK cell subsets compared to peripheral blood. The cytotoxic potential was significantly higher in PD-1- decidual immune cells compared to the periphery, however we measured a significantly lower cytotoxicity in the decidual PD-1+ CD8+ T cells compared with the peripheral subsets. An activation receptor NKG2D expression was decreased by the PD-1+ CD8+ T subsets in the first trimester compared to non-pregnant condition but the expression level of the decidual counterparts was significantly elevated compared to the periphery. The cytotoxic potential of decidual PD1/NKG2D double positive CD8+ T cells was significantly decreased compared to the peripheral subsets. Conclusions Based on our results we assume that PD-1/PD-L1 pathway might have a novel role in the maintaining of the local immunological environment. Accompanied by NKG2D activating receptor this checkpoint interaction could regulate decidual CD8 Tc cell subsets and may contribute maternal immunotolerance.

The Role of B7 Family Molecules in Maternal–Fetal Immunity

“…These results indicate that the PD-1/PD-L1 pathway might play a novel role in maintaining the local immunological environment. This immune checkpoint, accompanied by the activation receptor NKG2D, can regulate decidual CD8 + Tc cell subsets and contribute to maternal immunotolerance (53). A previous analysis showed that B7-H1 is unique to CD14 + decidual macrophages isolated from early pregnancy but is not observed on term or peripheral macrophages.…”

PDL1 blockage increases fetal resorption and Tfr cells but does not affect Tfh/Tfr ratio and B-cell maturation during allogeneic pregnancy

“…The engagement of PD-1 and its prior binding ligand programmed death ligand-1 (PDL1) recruits second signals required for T cell exhaustion that are characterized by reduced proliferation, diminished cytokine production, and functionally silenced cytotoxic effector, serving as a negative checkpoint for proper immune responses 7,8 . Several reports have proposed the importance of PD-1-PDL1 interaction involved in pregnancy maintenance, and increased PD-1 expression was detected in decidual immune cells in the first trimester of normal pregnancy 9,10 . In addition, previous studies have established links among PD-1 and PDL1 expression, Th1/Th2/Th17 balance and fetomaternal tolerance 11,12 .…”

Unveiling the pathophysiology of gestational diabetes: Studies on local and peripheral immune cells

“…The γδT cells and NKT cells seem to participate both in the maternal‐foetal interaction . Altered numbers of these cells have been observed in the decidua of women with recurrent miscarriage (RM) and in PB of patients with metabolic diseases …”

“…8 The γδT cells and NKT cells seem to participate both in the maternal-foetal interaction. [9][10][11][12] Altered numbers of these cells have been observed in the decidua of women with recurrent miscarriage (RM) and in PB of patients with metabolic diseases. 13 NK cells are involved in pregnancy development; in PB, most are CD16 + CD56 dim acting mainly through cytotoxicity.…”