Abstract
Mucosal-associated invariant T (MAIT) cells are an innate-like T cell subset with proinflammatory and cytotoxic effector functions. During pregnancy, modulation of the maternal immune system, both at the fetal-maternal interface and systemically, is crucial for a successful outcome and manifests through controlled enhancement of innate and dampening of adaptive responses. Still, immune defenses need to efficiently protect both the mother and the fetus from infection. So far, it is unknown whether MAIT cells are subjected to immunomodulation during pregnancy, and characterization of decidual MAIT cells as well as their functional responses during pregnancy are mainly lacking. We here characterized the presence and phenotype of Vα7.2+CD161+ MAIT cells in blood and decidua (the uterine endometrium during pregnancy) from women pregnant in the 1st trimester, i.e., the time point when local immune tolerance develops. We also assessed the phenotype and functional responses of MAIT cells in blood of women pregnant in the 3rd trimester, i.e., when systemic immunomodulation is most pronounced. Multi-color flow cytometry panels included markers for MAIT subsets, and markers of activation (CD69, HLA-DR, Granzyme B) and immunoregulation (PD-1, CTLA-4). MAIT cells were numerically decreased at the fetal-maternal interface and showed, similar to other T cells in the decidua, increased expression of immune checkpoint markers compared with MAIT cells in blood. During the 3rd trimester, circulating MAIT cells showed a higher expression of CD69 and CD56, and their functional responses to inflammatory (activating anti-CD3/CD28 antibodies, and IL-12 and IL-18) and microbial stimuli (Escherichia coli, group B streptococci and influenza A virus) were generally increased compared with MAIT cells from non-pregnant women, indicating enhanced antimicrobial defenses during pregnancy. Taken together, our findings indicate dual roles for MAIT cells during pregnancy, with an evidently well-adapted ability to balance the requirements of immune tolerance in parallel with maintained antimicrobial defenses. Since MAIT cells are easily activated, they need to be strictly regulated during pregnancy, and failure to do so could contribute to pregnancy complications.
Highlights
Pregnancy poses a unique challenge to the maternal immune system due to the semi-allogeneic nature of the fetus
Being described as innate-like T cells, our findings indicate that Mucosal-associated invariant T (MAIT) cells balance the dual requirements during pregnancy: in the decidua, MAIT cells are regulated in similarity to conventional T cells, while circulating MAIT cells show enhanced functional responses similar to innate immune cells
Decidual mononuclear cells and peripheral blood mononuclear cells (PBMCs) were analyzed by flow cytometry, and MAIT cells were defined by expression of the semi-invariant T cell receptor (TCR) chain Va7.2 as well as the C-type lectin receptor CD161 (Figure 1A)
Summary
Pregnancy poses a unique challenge to the maternal immune system due to the semi-allogeneic nature of the fetus. The numbers and activity of innate immune cells (monocytes, dendritic cells and neutrophils) were found to increase, while lymphocytes decreased [1, 4, 5] These systemic immune alterations could explain clinical phenomena observed during pregnancy: Firstly, pregnant women, especially during the 3rd trimester, are more susceptible to infections such as Listeria monocytogenes, influenza and herpes simplex virus, which are typically dependent on Th1 responses. Pregnant women with autoimmune diseases such as multiple sclerosis and rheumatoid arthritis experience a significant alleviation of symptoms and a transient decrease in relapse rate during the 3rd trimester [6, 7] Combined, these observations demonstrate that the maternal immune system undergoes immunomodulation during pregnancy, at the fetal-maternal interface and at a systemic level
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