Human uterine lymphocytes acquire a more experienced and tolerogenic phenotype during pregnancy

Marilen Benner,Olivier W. H. van der Heijden,Bram van Cranenbroek,Irma Joosten,Dorien Feyaerts,Renate G. van der Molen

doi:10.1038/s41598-017-03191-0

Marilen Benner, Olivier W. H. van der Heijden + Show 4 more

Open Access

https://doi.org/10.1038/s41598-017-03191-0

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Abstract

Pregnancy requires a delicate immune balance that nurtures the allogeneic fetus, while maintaining reactivity against pathogens. Despite increasing knowledge, data is lacking on the transition of pre-pregnancy endometrial lymphocytes to a pregnancy state. Here, we immunophenotyped lymphocytes from endometrium (MMC), term decidua parietalis (DPMC), and PBMC for direct comparison. We found that the immune cell composition of MMC and DPMC clearly differ from each other, with less NK-cells, and more NKT-cells and T-cells in DPMC. An increased percentage of central memory and effector memory T-cells, and less naive T-cells in DPMC indicates that decidual T-cells are more experienced than endometrial T-cells. The increased percentage of CD4+CD25highCD127− Treg in DPMC, including differentiated Treg, is indicative of a more experienced and tolerogenic environment during pregnancy. The Th cell composition of both MMC and DPMC was different from PBMC, with a preference for Th1 over Th2 in the uterine environment. Between MMC and DPMC, percentages of Th cell subsets did not differ significantly. Our results suggest that already before pregnancy a tightly controlled Th1/Th2/Th17 balance is present. These findings create opportunities to further investigate the underlying immune mechanism of pregnancy complications using menstrual blood as a source for endometrial lymphocytes.

Highlights

Pregnancy requires a complex interplay of immune cells
Since cell yield from decidua basalis was too low for the extensive analysis we did here, maternal lymphocytes in the decidua parietalis are in close contact with chorionic trophoblast cells, and active immune regulation seems to place at the decidua parietalis as well[28, 29], prompted our decision to opt for isolation of cells from decidua parietalis to study the fetal-maternal interface
In accordance with previous studies, MMC and DPMC clearly differ from peripheral blood mononuclear cells (PBMC) in percentages of lymphocytes, T cells, Natural killer (NK) cells and NKT cells[7,8,9, 27, 30, 31], and contained primarily CD56+CD16−NK cells, while the majority of NK cells in PBMC were CD56+/−CD16+

Summary

Introduction

Pregnancy requires a complex interplay of immune cells. Maternal lymphocytes need to accommodate the semi-allogeneic fetus and still maintain robust immune reactivity against pathogens. Direct response to fetal allogeneic HLA is primarily via HLA-C, and indirect presentation of fetal antigens by maternal APCs can elicit an anti-fetal maternal leukocyte response[2,3,4,5,6] This restricted immune recognition makes that the uterine immune cell composition and phenotype is different from other mucosal sites[1]. Endometrium will transform into decidua and the number of endometrial NK cells will increase even further and will make up 70% of the decidual leukocytes during the first trimester. These uterine NK cells are different from NK cells found in peripheral blood. The results of this study will provide us with a more profound insight into which adaptations of the uterine immune system during pregnancy are important for pregnancy success

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