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Early pregnancy is marked by placentation and embryogenesis, which take place under physiological low oxygen concentrations. This oxygen condition is crucial for many aspects of placentation, trophoblast function, vascularization and immune function. Recently, a new family of innate lymphoid cells has been found to be expressed at the fetomaternal interface. Among these, type 3 innate lymphoid cells (ILC3) are important antigen presenting cells in the context of MHC-II. The expression of MHC-II on ILC3s during pregnancy is reduced. We tested the hypothesis that low oxygen concentrations reduce the potential of ILC3s to present antigens promoting fetal tolerance.
Using an in vitro approach, NCR+ ILC3s generated from cord blood stem cell precursors were incubated under different O2 concentrations in the presence or absence of the pregnancy-related hormones hCG and TGF-β1. The expression of MHC-II, accessory molecules and an activation marker were assessed by flow cytometry. We observed that 1% O2 reduced the expression of the MHC-II molecule HLA-DR as compared to 21% O2 and modulated the relative effects of hCG and TGF-β1.
Our data indicate that low oxygen concentrations reduce the antigen presentation potential of NCR+ ILC3s and suggest that it may promote fetal tolerance during the first trimester of pregnancy.
Pregnancy involves adaptations of the cellular composition in utero to establish a functioning fetal-maternal interface. Different subsets of leukocytes populate the endometrium and contribute to tolerance of the fetal allograft while protecting it from potentially threatening infections or rejection. ¬¬Innate lymphoid cells are recently discovered immune cells that, besides the gut, lung and skin, possess immunoregulatory functions in the female reproductive tract, especially during gestation. Although present at the fetal-maternal interface, the dynamics of ILC migration during pregnancy remains poorly investigated. The involvement of homing receptors in ILC migration to the uterus was the main subject of the present work.
First, the expression of homing receptors on ILCs from miscellaneous organs was assessed across the course of murine pregnancy in vivo by means of flow cytometry. Then, their migratory capacity towards pregnancy-relevant chemokines was investigated in vitro. The impact of pregnancy related hormones on the migration and homing of ILCs was then analysed in vitro via migration assays.
The results confirm altered proportions of ILCs in utero and the altered expression of homing receptors in ILCs in pregnancy. Different murine lymphoid organs showed augmented expression of chemokine receptors and decreased levels of homing integrin α4β7 in the first trimester, suggesting enhanced migration patterns of ILCs during early pregnancy. Subsequently, migration assays were used to demonstrate the role of different chemokine ligands in enhancing ILC migration.
Eventually, the alterations in homing receptor expression were correlated with female pregnancy hormones. Progesterone treatment caused similar effects on homing receptor expression in ILCs as observed during early gestation. These results represent the first study evaluating the effect of sex steroid hormones on ILC chemokine receptor distribution.
Taken together, our results indicate the involvement of pregnancy-relevant chemokines, including CCL4, CCL20 and CCL28, in the recruitment of ILCs to the uterus during pregnancy. The data highlight an endocrinological-immune crosstalk in the regulation of ILC homing to the female reproductive tract. Gestation alters chemokine receptor expression in order to regulate the access of immune cell subsets to the fetal-maternal interface. An adequate regulation is highly needed, as a lack or abundance of different subgroups could result in pregnancy complications, including fetal loss, pre-eclampsia or pre-term birth. Thus, the role of ILC chemotaxis to the pregnant uterus and its regulation are of interest in the understanding, prevention and treatment of the clinically relevant obstetric diseases.