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Decidual CD4 + T (dCD4 + T) cells play pivotal roles in inducing and maintaining maternal-fetal tolerance. Dysfunctional dCD4 + T cells are associated with miscarriage. In the present study, we demonstrated that the T-box transcription factor protein eomesodermin (Eomes) was involved in the functional regulation of dCD4 + T cells during early pregnancy. We concluded the higher Eomes expression dCD4 + T cells during normal pregnancy, and the Eomes + dCD4 + T cells displayed an active status and produced more Th2- and Treg type cytokines. Decreased number and altered function of Eomes + dCD4 + T cells were observed in miscarriage. Progesterone, the traditional treatment for miscarriage, had no effect on Eomes expression by dCD4 + T cells from normal pregnancy, but increased Eomes expression by dCD4 + T cells from miscarriage. We also found the higher frequency of Eomes + dCD4 + T cells from miscarriage in response to cyclosporine, tacrolimus, Trophoblasts, and HTR8/SVneo cell line, might provide new strategy for therapy to promote maternal-fetal tolerance and prevent pregnancy loss. These results indicated that Eomes might be promising early warming targets of miscarriage, though further studies are required to determine that the altered number and function of Eomes + dCD4 + T cells are the cause or consequence of miscarriage., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

To obtain a successful pregnancy, the establishment of maternal-fetal tolerance and successful placentation are required to be established. Disruption of this immune balance and/or inadequate placental perfusion is believed to be associated with a lot of pregnancy-related complications, such as recurrent spontaneous abortion, pre-eclampsia, and fetal intrauterine growth restriction. Extravillous trophoblasts (EVTs) have the unique ability to instruct decidual immune cells (DICs) to develop a regulatory phenotype for fetal tolerance. Utilizing immortalized human first trimester extravillous trophoblast cells and primary EVTs, we found that DICs promote EVT function and placental development. We have previously shown that checkpoints T-cell immunoglobulin mucin-3 (Tim-3) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are important for DIC function. In the present study, we showed that blockade of Tim-3 and CTLA-4 pathways leaded to the abnormal DICs-EVTs interaction, poor placental development, and increased fetal loss. Treatment with IL-4 and IL-10 could rescue the adverse effects of targeting Tim-3 and CTLA-4 on the pregnancy outcome. Hence, the reproductive safety must be a criterion considered in the assessment of immuno-therapeutic agents. In addition, IL-4 and IL-10 may represent novel therapeutic strategies to prevent pregnancy loss induced by checkpoint inhibition., (© 2021 Federation of American Societies for Experimental Biology.)

The aim of the current study was to determine the pattern of immune cells and related functional molecules in peripheral blood and at the maternal-fetal interface in women with unexplained recurrent spontaneous abortion (URSA). In part I, 155 women were included and divided into four groups: non-pregnant controls with no history of URSA (NPCs), pregnant controls with no history of URSA (PCs), non-pregnant women with a history of URSA (NPUs), and pregnant women with a history of URSA (PUs). Venous blood samples were collected and analyzed. In part II, 35 subjects with URSA and 40 subjects in the early stage of normal pregnancy who chose to undergo an abortion were recruited. Samples of the decidua were collected, and the proportion of immune cells and the expression of related molecules were evaluated. Peripheral regulatory T cells (Treg cells) increased in PCs compared to NPCs, but in women with URSA the flux of Treg cells disappeared when pregnancy occurred. Levels of interleukin-10 (IL-10), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and IL-17 and the ratio of Th17/Treg cells in peripheral blood remained stable among the four groups. At the maternal-fetal interface, the percentage of Treg cells, the level of CTLA-4 of CD4 + CD25 + CD127 lo cells and CD4 + Foxp3 + cells were significantly lower in women with URSA compared to controls, respectively. Levels of transforming growth factor-β1 (TGF-β1) mRNA and protein in the decidua significantly decreased in URSA while levels of IL-6 and tumor necrosis factor-ɑ (TNF-ɑ) and the Th17/Treg ratio significantly increased. In conclusion, peripheral Treg cells did not increase in pregnant women with URSA. The decrease in Treg cells and levels of CTLA-4 and TGF-β1 and as well as the increase in levels of IL-6 and TNF-ɑ, and the Th17/Treg ratio at the maternal-fetal interface might contribute to inappropriate maternal-fetal immune tolerance in URSA.