Regulatory T Cells in Pregnancy: It Is Not All About FoxP3

Juliette Krop, Sebastiaan Heidt, Frans H J Claas, Michael Eikmans, Juliette Krop, Sebastiaan Heidt, Frans H J Claas, Michael Eikmans

Abstract

In pregnancy, the semi-allogeneic fetus needs to be tolerated by the mother's immune system. Regulatory T cells (Tregs) play a prominent role in this process. Novel technologies allow for in-depth phenotyping of previously unidentified immune cell subsets, which has resulted in the appreciation of a vast heterogeneity of Treg subsets. Similar to other immunological events, there appears to be great diversity within the Treg population during pregnancy, both at the maternal-fetal interface as in the peripheral blood. Different Treg subsets have distinct phenotypes and various ways of functioning. Furthermore, the frequency of individual Treg subsets varies throughout gestation and is altered in aberrant pregnancies. This suggests that distinct Treg subsets play a role at different time points of gestation and that their role in maintaining healthy pregnancy is crucial, as reflected for instance by their reduced frequency in women with recurrent pregnancy loss. Since pregnancy is essential for the existence of mankind, multiple immune regulatory mechanisms and cell types are likely at play to assure successful pregnancy. Therefore, it is important to understand the complete microenvironment of the decidua, preferably in the context of the whole immune cell repertoire of the pregnant woman. So far, most studies have focused on a single mechanism or cell type, which often is the FoxP3 positive regulatory T cell when studying immune regulation. In this review, we instead focus on the contribution of FoxP3 negative Treg subsets to the decidual microenvironment and their possible role in pregnancy complications. Their phenotype, function, and effect in pregnancy are discussed.

Keywords: HLA-G Treg; Th3 regulatory cells; Tr1 regulatory cells; immune tolerance; preeclampsia; pregnancy; recurrent pregnancy loss (RPL); regulatory T (Treg) cells.

Copyright © 2020 Krop, Heidt, Claas and Eikmans.

Figures

Figure 1
Figure 1
Schematic overview of the maternal-fetal interface at different trimesters. (A) During first-trimester, the maternal immune cells in the decidua can come into contact with fetal syncytiotrophoblasts, when around weeks 11–12 the maternal blood flow commences (B) a second maternal-fetal interface occurs. The maternal immune cells in the periphery can come into contact with fetal syncytiotrophoblasts, while the maternal decidual immune cells are in contact with the fetal extravillous trophoblasts. Indicating immunotolerance needs to adapt during the shift in gestation.
Figure 2
Figure 2
Main tolerogenic mechanisms of the FoxP3−HLA-G+ regulatory T cell. HLA-G+ regulatory T cells can suppress in a cell-contact dependent manner via HLA-G1. It inhibits the killing capacity of T cells and NK cells, downregulates HLA class II, CD80, and CD86 in DCs and macrophages, and makes them tolerogenic by inducing IDO production in macrophages and the induction of DCs to DC-10 cells. HLA-G+ regulatory T cells produce IL-10 and soluble HLA-G5 that helps to create a tolerogenic decidual microenvironment. HLA, human leukocyte antigen; NK, natural killer cell; DC, dendritic cell; IDO, indoleamine 2,3-dioxygenase; IL-10, interleukin-10; DC-10, tolerogenic DCs.
Figure 3
Figure 3
Main tolerogenic mechanisms of the Tr1 regulatory T cell. Tr1 regulatory T cells can in a cell-contact dependent manner lyse APCs via their KIR receptors and disturb the metabolic state of T cells. They produce IL-10 and TGF-β that helps to create a tolerogenic decidual microenvironment. APC, antigen-presenting cell; KIR, killer-cell immunoglobulin-like receptor; IL-10, interleukin-10; TGF-β, transforming growth factor-beta.
Figure 4
Figure 4
Main tolerogenic mechanisms of the Th3 regulatory T cell. Th3 regulatory T cells suppress in a cell-contact independent mechanism only by the production of TGF-β, IL-10 and differ here from the Tr1 regulatory T cell by the production of IL-4. TGF-β, transforming growth factor-beta; IL, interleukin.
Figure 5
Figure 5
Overview of FoxP3− immune regulating T cells discussed in this review and their main tolerogenic mechanisms in pregnancy. All Tregs described in this review can exert immunosuppressive properties in a cell-contact independent mechanism that together contributes to a tolerogenic decidual microenvironment. Next to that, the HLA-G+ Treg, Tr1 Treg, and CD8+ Treg can exert their immunosuppressive properties in a cell-contact dependent mechanism.

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Source: PubMed

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