Three types of HLA-G+ extravillous trophoblasts that have distinct immune regulatory properties

Abstract

<jats:p>During pregnancy, invading HLA-G+ extravillous trophoblasts (EVT) play a key role in placental development, uterine spiral artery remodeling, and prevention of detrimental maternal immune responses to placental and fetal antigens. Failures of these processes are suggested to play a role in the development of pregnancy complications, but very little is known about the underlying mechanisms. Here we present validated methods to purify and culture primary HLA-G+ EVT from the placental disk and chorionic membrane from healthy term pregnancy. Characterization of HLA-G+ EVT from term pregnancy compared to first trimester revealed their unique phenotypes, gene expression profiles, and differing capacities to increase regulatory T cells (Treg) during coculture assays, features that cannot be captured by using surrogate cell lines or animal models. Furthermore, clinical variables including gestational age and fetal sex significantly influenced EVT biology and function. These methods and approaches form a solid basis for further investigation of the role of HLA-G+ EVT in the development of detrimental placental inflammatory responses associated with pregnancy complications, including spontaneous preterm delivery and preeclampsia.</jats:p>

First immunotherapeutic CAR-T cells against the immune checkpoint protein HLA-G

“…HLA-G is also involved in the generation of a tumor tolerogenic microenvironment through regulatory cells: its expression is correlated with accumulation of MDSC, 61 increased CD4 + CD25 + FoxP3 + population 62 and secretion of IL-10 and TGF-β that are responsible for the TME maintenance. 17 Furthermore, HLA-G is expressed by tolerogenic immune cells such as CD4 + FoxP3 - HLA-G + Treg, 63 suppressive NK cells, 30 DC-10 cells, 64 infiltrating monocytes 65 and tumor-associated macrophages (TAM), 66 67 all involved in the TME. We did not formally demonstrate in the present manuscript that anti-HLA-G CAR-T cells were capable of killing real ex vivo tolerogenic HLA-G-expressing cells such as DC-10 cells.…”

Roles of HLA-G in the Maternal-Fetal Immune Microenvironment

“…This proportion has been shown to rise up to 70% at the end of pregnancy (77). At the same time, HLA-G expression has been observed to be higher in term pregnancy EVT cells than in firsttrimester EVTs (91). Decidual T cells have been reported to express the HLA-G receptor ILT2.…”

A Brief Analysis of Tissue-Resident NK Cells in Pregnancy and Endometrial Diseases: The Importance of Pharmacologic Modulation

“…In aged mouse and humans, the resolution of endometriosis is delayed [34]. Chronic inflammation in endometrial tissue decreases the telomerase activity of several cells, impeding their optimal physiological response in mouse [34] and humans [21,[35][36][37][38][39]. trNK cells could also be affected by the low telomerase response [34].…”

“…trNK cells could also be affected by the low telomerase response [34]. On the other hand, senescent cells may activate the cytotoxic response of cNK cells [34][35][36][37][38][39] against autologous cells and, in consequence, generate more cell death maintaining the local chronic inflammatory response.…”

“…In humans, NK cells, macrophages, and T cells are responsible for maintaining the local inflammatory response [35][36][37][38][39][40]. The role of TH17 and IFN γ has been widely discussed; however, the control of inflammation in the tissue is not achieved in many patients despite surgery or other therapeutic options raising the question of a wider variety of endometrial diseases [21,[36][37][38][39]. One of the often-overlooked events is autoantibodies, which can play an essential role in maintaining the inflammatory response [40][41][42].…”