Abstract
The perfect synchronization of maternal immune-endocrine mechanisms and those of the fetus is necessary for a successful pregnancy. In this report, decidual immune cells at the maternal-fetal interface were detected that expressed TIGIT (T cell immunoreceptor with Ig and ITIM domains), which is a co-inhibitory receptor that triggers immunological tolerance. We generated recombinant TIGIT-Fc fusion proteins by linking the extracellular domain of TIGIT and silent Fc fragments. The treatment with TIGIT-Fc of human decidual antigen presenting cells (APCs), the decidual dendritic cells (dDCs), and decidual macrophages (dMϕs) increased the production of interleukin 10 and induced the decidua APCs to powerfully polarize the decidual CD4+ T cells toward a classic TH2 phenotype. We further proposed that Notch signaling shows a pivotal effect on the transcriptional regulation in decidual immune cell subsets. Moreover, the administration of TIGIT-Fc to CBA/J pregnant mice at preimplantation induced CD4+ forkhead box P3+ (Foxp3+) regulatory T cells and tolerogenic dendritic cells and increased pregnancy rates in an abortion-prone animal model stress. The results suggested the therapeutic potential of the TIGIT-Fc fusion protein in reinstating immune tolerance in failing pregnancies.
Highlights
A successful pregnancy is a unique type of immunological process in which the semiallogeneic paternal antigens carried by the fetus are accepted by the maternal immune system, allowing trophoblasts to invade
The results suggested the therapeutic potential of the TIGIT-Fc fusion protein in reinstating immune tolerance in failing pregnancies
The high expression of TIGIT was detected in CD4+CD25hi T cells, memory CD45RO+ cells and Decidual NK cells (dNK) cells, while naive CD45RA+ T cells, DC cells and decidual CD14+ monocytes/ macrophages showed low levels of TIGIT mRNA expression (Figure 1A)
Summary
A successful pregnancy is a unique type of immunological process in which the semiallogeneic paternal antigens carried by the fetus are accepted by the maternal immune system, allowing trophoblasts to invade. The defense mechanisms against pathogens in the maternal immune system are preserved. The mechanisms regulating these unique immunological behaviors and maintaining the harmonious coexistence of maternal- and fetal-derived cells remain poorly understood [1]. Given that the dysregulation of maternal–fetal immunity and deficient placentation have a notable relationship with pregnancy loss and pregnancy complications, such as fetal growth restriction (FGR) [2], recurrent pregnancy loss (RPL) [3], and pre-eclampsia (PE) [4], further studies to advance the diagnosis and prevention of these conditions are urgently needed. During the past few decades, growing evidence has proven the inevitable role of a misdirected maternal immune response in PRL.
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