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ORIGINAL ARTICLE
Ahead of print publication  

Altered carcinoembryonic antigen-related cell adhesion molecule 1/T-Cell immunoglobulin mucin-3 signaling causes the dysregulation of decidual CD8+T cells in the third trimester during preeclamptic pregnancies


1 Laboratory for Reproductive Immunology, NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China
2 Department of Obstetrics, Obstetrics and Gynecology, Hospital of Fudan University, Shanghai 200090, China

Date of Submission26-May-2021
Date of Decision23-Jun-2021
Date of Acceptance02-Aug-2021
Date of Web Publication09-Sep-2021

Correspondence Address:
Ying Zhang,
Department of Obstetrics, Obstetrics and Gynecology, Hospital of Fudan University, No. 128 Shenyang Road, Shanghai 200090
China
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2096-2924.325828

  Abstract 


Objective: To investigate the frequency and function of Tim-3+CD8+T cells in the third trimester of normal pregnancies (NPs) and preeclamptic (PE) pregnancies.
Methods: T-cell immunoglobulin mucin-3 (Tim-3) expression levels of CD8+T cells in the decidua, peripheral blood, and umbilical cord blood obtained from women showing NPs and PE pregnancies were analyzed using flow cytometry. Decidual CD8+T cells were cultured in the presence of recombinant human carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) protein and/or Tim-3-specific neutralizing antibodies for analyzing CD107a and intracellular cytokine expression. The placental CEACAM1 protein expression was analyzed using immunohistochemistry.
Results: Tim-3+CD8+T cells were more abundant in the decidua than in the peripheral blood. Tim-3 expression in the decidual CD8+T cells was significantly lower in PE patients. Decidual Tim-3+CD8+T cells from PE patients expressed higher levels of CD107a and the Th1-type cytokine IFN-γ, but lower levels of the Th2-type cytokine IL-4. CEACAM1 altered the CD107a, IFN-γ, and IL-4 levels; this was reversed by anti-Tim-3 antibodies. The CEACAM1 protein levels were lower in the placental tissues of women with PE pregnancies than in those of women with NPs.
Conclusions: Abnormal CEACAM1/Tim-3 regulation may participate in the development of PE, accompanied by disturbed Th2 cell predominance and higher cytotoxicity of decidual CD8+T cells.

Keywords: 3rd-trimester; Carcinoembryonic Antigen-related Cell Adhesion Molecule 1; CD8+T Cells; Preeclampsia; Tim-3



How to cite this URL:
Chen CQ, Wang SC, Sun FR, Li MD, Du MR, Zhang Y. Altered carcinoembryonic antigen-related cell adhesion molecule 1/T-Cell immunoglobulin mucin-3 signaling causes the dysregulation of decidual CD8+T cells in the third trimester during preeclamptic pregnancies. Reprod Dev Med [Epub ahead of print] [cited 2021 Oct 20]. Available from: https://www.repdevmed.org/preprintarticle.asp?id=325828




  Introduction Top


Preeclampsia (PE), a primary cause of maternal and prenatal mortality and morbidity, is a severe and common obstetric disorder that affects 5%–8% of pregnant women worldwide. It is defined as high blood pressure combined with proteinuria or other systemic disorders (such as thrombocytopenia, elevated levels of liver transaminases, renal insufficiency, pulmonary edema, and visual or cerebral disturbances) at or after the 20th week of gestation.[1] As PE is a life-threatening disease and lacks effective treatment, there is a pressing need to understand its pathogenesis and identify early biomarkers and effective therapeutic strategies for protecting both mothers and their babies.

Apart from insufficient trophoblast invasion and spiral artery remodeling disorder, PE is also characterized by a systemic maternal inflammatory response with the involvement of the immunoactivation associated with elevated levels of inflammatory cytokines.[2],[3] During normal pregnancy (NP), the maternal immune system undergoes numerous changes to allow the semi-allogeneic fetus to peacefully coexist with the mother and protect the woman against pathogens. Failure to maintain proper crosstalk at the maternal–fetal interface, however, causes the placenta and fetus to be attacked as a foreign organ transplant, resulting in pregnancy-associated complications such as PE and spontaneous abortion.[4] CD8+T cells, the most abundant T-cell subset in the decidua, also participate in the maintenance of pregnancy. Recently, Morita et al. demonstrated that an aberrant T-cell receptor repertoire and the downregulation of PD-1 in the peripheral blood CD8+T (pbCD8+T) cells revealed distinct immune mechanisms in PE.[5] Smith et al. also found that abnormal infiltration of CD8+T cells into the placental villous tissue occurred during both fetal growth restriction and PE.[5],[6] Therefore, CD8+T cells play a major role in immunoregulatory mechanisms, both at the cellular and molecular levels in PE.

T-cell immunoglobulin mucin-3 (Tim-3) was originally identified as a surface molecule that terminates T helper 1 and interferon-γ-producing cytotoxic cell responses. Moreover, recent reports show that upon activation, Tim-3 is widely expressed by different lymphocyte subsets (T-cells, B-cells, and NK-cells) and by antigen-presenting cells, playing critical roles in regulating immune activities during infection, tumor growth, and organ transplantation.[7],[8] Abnormal expression of Tim-3 was observed in miscarriages. During early pregnancy, the Tim-3 signaling pathway is thought to be associated with the promotion of Th2 cell bias and regulatory T-cell expansion.[9],[10],[11],[12] Blockade of Tim-3 also results in an accumulation of inflammatory CD8+T cells and the upregulation of pro-inflammatory cytokines at the maternal–fetal interface.[12],[13] However, little is known about the involvement of Tim-3–mediated immunoregulation in the middle and late stages of pregnancy and in pregnancy-related disorders. The features of Tim-3 coincide with the paradigm of immune balance during pregnancy.

In the current study, we demonstrated that increased Tim-3 expression in the decidual CD8+T cells (dCD8+T cells) is an intrinsic event in human pregnancy; this event occurs via the fine-tuning of the normal adaptive immune defense. A decreased percentage of decidual Tim-3+ CD8+T cells were accompanied by a disturbed Th2 cell predominance and higher cytotoxicity during PE. Considering that carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) may be the main ligand associated with Tim-3 activation in dCD8+T cells, abnormal CEACAM1/Tim-3 signaling may be involved in the development of PE.


  Materials and Methods Top


Sample collection and patient clinical characteristics

The use and collection of human samples were approved by the Human Research Ethics Committee of the Obstetrics and Gynecology Hospital of Fudan University (EC 2019-69). All participants provided written informed consent. All methods were carried out in accordance with the approved guidelines. Twenty-eight pregnant women diagnosed with PE were included, according to the ACOG guidelines: systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg on two occasions at least 4 h after 20 weeks of gestation, with proteinuria or accompanied by one of the following conditions: platelet count <100,000/μL; transaminase levels more than twice the normal value; creatinine ≥1.1 mg/dL; pulmonary edema; and new neurological abnormalities.[14] Thirty-five healthy pregnant women in the third trimester of pregnancy were recruited as members of the NP group. None of the healthy women had any significant medical history or current or recent illnesses or were taking medications. The decidual tissues, peripheral blood, and umbilical cord blood were collected from the volunteers during delivery. Women with NPs in the third trimester were matched with the women with PE with regard to age, gestational age, and body mass index [Table 1].

Cell treatment

Decidual immune cells were obtained from the decidual tissues of women with NPs and those with PE. The decidual tissues were cut and digested in RPMI 1640 supplemented with collagenase type IV (1.0 mg/mL, CLS-1, Worthington Biomedical) and DNase I (150 U/mL, Applichem). The suspension was filtered and enriched by discontinuous Percoll gradient centrifugation, as described previously.[15] CD8+T cells were isolated by magnetic affinity cell sorting using CD8 microbeads (Miltenyi Biotec, Germany). Peripheral blood mononuclear cells (PBMCs) and umbilical cord blood mononuclear cells were obtained using a Ficoll solution.

Decidual CD8+T cells were cultured (5 × 105 per well) in the presence of recombinant human Galectin 9 (1 μg/mL, R and D Systems, Minneapolis, MN, USA), CEACAM1 (1 μg/mL, R and D Systems, Minneapolis, MN, USA), high mobility group protein B1 (HMGB1; 1 μg/mL, R and D Systems, Minneapolis, MN, USA), neutralizing antibodies against Tim-3 (10 μg/ml, clone F38-2E2, BioLegend), and the isotype control (IgG). CD8+T cells were also pretreated with plate-bound anti-CD3 antibodies (OKT-3, 5 μg/mL) plus anti-CD28 antibodies (28.2, 1 μg/mL). For intracellular cytokine analysis, brefeldin A (10 mg/mL, BioLegend, USA), phorbol 12-myristate 13-acetate (PMA) (50 ng/mL), and ionomycin (1 μg/mL) were added for 4 h before the end of the 48-h culture.

Flow cytometry

A total of 1 × 106 decidual CD8+T cells were resuspended with PBS and stained with FITC-conjugated anti-human CD45, CD3, CD8, and CD107a, PE-conjugated anti-human Tim-3, PE/CY7-conjugated anti-human CD8, TNF-α, IFN-γ, TGF-β1, CCR7, and CD69, APC-conjugated anti-human CD45, CD8, IL-10, and IL-4, brilliant violet 421-conjugated anti-human CD3 and CD127, and brilliant violet 510-conjugated anti-human HLA-DR and CD45RA (BioLegend, CA, USA). A minimum of 10,000 events were recorded using a CyAn ADP flow cytometer (Beckman–Coulter, CA, USA); the flow cytometric data were analyzed using the FlowJo software (Tree Star, OR, USA).

Immunohistochemistry

After antigen retrieval, the paraffin-embedded placental tissue sections were incubated with rabbit anti-human CEACAM1 (ab108397, Abcam, Cambridge, UK) using standard immunohistochemical techniques, according to the manufacturer's instructions. Expression of CEACAM1 protein was assessed by the following method: the index of CEACAM1 expression was calculated as the intensity of the staining (0–3) multiplied by the percentage of positively stained cells (0–3).

Statistical analysis

Statistical analyses were performed using the Statistical Package for the Social Science (SPSS) for Windows (SPSS Inc., Chicago, IL, USA) and GraphPad Prism software, version 8 (GraphPad, San Diego, CA, USA). Differences in continuous variables between the two study groups were analyzed using the Mann–Whitney or t-test, depending on the normality of the distribution, which was assessed using the Shapiro–Wilk test. One-way analysis of variance (ANOVA) was used to evaluate the differences between multiple groups. Statistical significance was set at P < 0.05. For variables with a P < 0.05, the post hoc Dunnett t-test was performed to determine the significance of the differences between each group.


  Results Top


Characterization of Tim-3+ decidual CD8+T cells during the third trimester of normal pregnancies

To investigate the regulation of Tim-3 signaling in decidual CD8+T cells, we first analyzed the expression of Tim-3 in these cells. The results in [Figure 1]a show that more than 20% of the decidual CD8+T cells expressed Tim-3. We also examined the expression of Tim-3 in pbCD8+T cells and umbilical cord blood CD8+T cells (uCD8+T cells) from pregnant women during the third trimester of pregnancy and found that the percentage of Tim-3-positive uCD8+T cells was approximately the same as that of Tim-3-positive decidual CD8+T cells. However, Tim-3 expression was significantly decreased in pbCD8+T cells [Figure 1]b.
Figure 1: Tim-3+CD8+T cells are present in human decidual tissues during the third trimester of pregnancy. Flow cytometric analysis (a) and measurement (b) of Tim-3 expression in CD8+T cells from decidual tissues, peripheral blood, and umbilical cord blood of healthy pregnant women during the third trimester of pregnancy. The data represent the mean ± standard error of the mean; *P < 0.05. dCD8+T cells: Decidual CD8+T cells, n = 35; pbCD8+T cells: Peripheral blood CD8+T cells, n = 15; uCD8+T cells: Umbilical cord blood CD8+T cells, n = 16; Tim-3: T-cell immunoglobulin mucin-3.

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To further explore the regulation of the expression of Tim-3 on decidual CD8+T cells during the third trimester in healthy pregnancy, we next compared the characterization of Tim-3+ and Tim-3dCD8+T cells. It was observed that Tim-3+CD8+T cells consisted of more effector memory cells (TCM, CD45RACCR7) and fewer central memory cells (TEM, CD45RACCR7+) than Tim-3CD8+T cells[16] [Figure 2]a. However, the expression of Ki67, a marker of proliferating cells, was lower in decidual Tim-3CD8+T cells than in decidual Tim-3+CD8+T cells [Figure 2]b. The expression of CD107a [a lysosome-associated membrane glycoprotein, [Figure 2]c] was much higher, suggesting that Tim-3CD8+T cells are more cytotoxic. The expression levels of HLA-DR, CD69, and CD127 [Figure 2]d were much higher in decidual Tim-3+CD8+T cells than in the negative group. After exposure to phorbol 12-myristate 13-acetate (PMA) and ionomycin for 4 h, the percentage of cells producing the Th1-type cytokines TNF-α and IFN-γ among the decidual Tim-3+CD8+T cells was reduced, compared with that among decidual Tim-3CD8+T cells [Figure 2]e. However, the production of immune-regulatory cytokines, including IL-4, TGF-β1, and IL-10, by decidual Tim-3+CD8+T cells increased significantly [Figure 2f]. These data suggest that decidual Tim-3+CD8+T cells show characteristics of immune tolerance during the late stage of pregnancy.
Figure 2: Characterization of Tim-3+decidual CD8+T cells from healthy pregnant women during the third trimester of pregnancy. (a) Decidual CD8+T cells obtained during the third trimester of pregnancy (n = 6) were stained with antibodies against CD8, CD45RA, CCR7, and Tim-3, and then analyzed by flow cytometry. (b-f) Quantitative flow cytometric analysis of Ki67 (b), CD107a (c), HLA-DR, CD69, and CD127 (d), and cytokine expression (e and f) in the decidual Tim-3+ and Tim-3CD8+T cells from healthy pregnant women during the third trimester of pregnancy. The data represent the mean ± standard error of the mean. The flow cytometry plots are representative of three independent experiments. n = 6; P < 0.05, P < 0.01, P < 0.001. dCD8+T cells: Decidual CD8+T cells; Tim-3: T-cell immunoglobulin mucin-3.

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A decreased percentage of decidual Tim-3+ CD8+T cells is accompanied by disturbed Th2 cell predominance and higher cytotoxicity during preeclampsia

First, we verified the critical role of Tim-3 in maintaining immune homeostasis. To obtain further evidence for the role of Tim-3 in dCD8+T cell function during late pregnancy, Tim-3 expression in the dCD8+T cells was detected in women with NPs and PE. The expression of Tim-3 in dCD8+T cells was significantly lower in the subjects with PE than in those with NP [Figure 3]a. Furthermore, decidual Tim-3+ CD8+T cells from subjects with PE expressed higher levels of CD107a [Figure 3]b and the Th1 type cytokine IFN-γ [Figure 3]c, but lower levels of the Th2-type cytokine IL-4 [Figure 3]d. These findings indicate that both the number and function of decidual Tim-3+CD8+T cells are abnormal in PE pregnancies.
Figure 3: Decidual Tim-3+CD8+T cells showed decreased numbers and disordered function in patients with PE. Expression levels of Tim-3 in CD8+T cells from the decidual tissues of women with NP (n = 35) and PE (n = 28) were analyzed by flow cytometry (a). Expression levels of CD107a (b), interferon-γ (c), and IL-4 (d) in decidual Tim-3+CD8+T cells from women with NP (n = 6) and PE (n = 6) were analyzed by flow cytometry. The data represent the mean ± standard error of the mean. *P < 0.05, P < 0.01, P < 0.001. NP: Normal pregnancy; PE: Preeclampsia; Tim-3: T-cell immunoglobulin mucin-3.

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T-cell immunoglobulin mucin-3 drives the immune tolerance of dCD8+T cells in conjunction with carcinoembryonic antigen-related cell adhesion molecule 1 during normal third-trimester pregnancies

Galectin 9 (Gal-9), CEACAM1, and HMGB1 have been reported to be ligands of Tim-3; they bind to different regions of the Tim-3 extracellular immunoglobulin V domain.[17] To further explore how Tim-3 was downregulated and rendered dysfunctional in PE pregnancies, we assessed the expression of Tim-3 after stimulation with the human recombinant Gal-9, CEACAM1, and HMGB1 proteins. After exposure to these recombinant proteins for 48 h, we found that only CEACAM1 significantly elevated the Tim-3 levels in dCD8+T cells [Figure 4]a, indicating that abnormal CEACAM1/Tim-3 signaling results in immune imbalance at the maternal–fetal interface.
Figure 4: Decidual Tim-3+CD8+T cells sustain immune tolerance in conjunction with CEACAM1. Decidual CD8+T cells from the third trimester of pregnancy (n = 6) were stimulated by treatment with the human recombinant Gal-9, CEACAM1, and HMGB1 proteins for 48 h. The expression of Tim-3 in CD8+T cells was analyzed by flow cytometry (a). Decidual CD8+T cells were treated with recombinant human CEACAM1 and/or anti-Tim-3 neutralizing antibodies. The expression levels of CD107a (b), IFN-γ (c), and IL-4 (d) in dCD8+T cells were analyzed by flow cytometry. The data represent the mean ± standard error of the mean. *P < 0.01, P < 0.001. CEACAM1: Carcinoembryonic antigen-related cell adhesion molecule 1.

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To verify this hypothesis, in vitro experiments were performed using dCD8+T cells obtained from the decidual tissues of women with NPs (third-trimester) during delivery, as it was impossible to administer anti-Tim-3 antibodies to pregnant women because of ethical constraints. We stimulated dCD8+T cells with anti-CD3/CD28 antibodies in the absence of recombinant human CEACAM1 (rhCEACAM1) and/or anti-Tim-3 neutralizing antibodies. Treatment with rhCEACAM1 decreased the CD107a and IFN-γ expression levels [Figure 4]b and [Figure 4]c but increased the production of the anti-inflammatory cytokine IL-4 by dCD8+T cells [Figure 4]d. These phenomena were reversed by anti-Tim-3 antibody treatment [Figure 4]b, [Figure 4]c, [Figure 4]d. However, anti-Tim-3 antibodies alone did not affect the expression of CD107a in, and IFN-γ and IL-4 production by, dCD8+T cells.

Decreased carcinoembryonic antigen-related cell adhesion molecule 1 expression in placental tissues from women with preeclampsia

We further evaluated CEACAM1 expression in placental tissues from women with PE and women with NP. We found that CEACAM1 was expressed in both cytotrophoblasts and syncytiotrophoblasts [Figure 5]a. As expected, the protein levels of CEACAM1 were lower in the placental tissues of subjects with PE than in the placental tissues of women with NPs [Figure 5b]. These results suggest a potential correlation between the CEACAM1/Tim-3 axis and immunologic imbalance at the maternal-fetal interface in PE.
Figure 5: CEACAM1 expression in placental tissues from women with NP and women with PE. Placental tissues were collected from women with NP (n = 11) and women with PE (n = 11). (a) The CEACAM1 expression levels in placental tissues were analyzed using immunohistochemistry (×200). (b) Comparison of CEACAM1 protein expression between women with NP and those with PE. *P < 0.05; NP: Normal pregnancy; PE: Preeclampsia; CEACAM1: Carcinoembryonic antigen-related cell adhesion molecule 1.

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  Discussion Top


Although PE is associated with high maternal and fetal morbidity and mortality worldwide, the mechanisms contributing to this life-threatening disease have not yet been fully elucidated. It is now clear that PE is a multifactorial syndrome, but not an isolated disease. Successful pregnancy relies on sufficient placental formation and the maternal immune system tolerating the semi-allogeneic fetus. Multiple mechanisms function to protect the fetus from attacks by the maternal immune system and promise adequate placental perfusion. Research on pathological pregnancy has provided clues about dynamic changes in immune cells at the maternal–fetal interface.[3] While many studies have described the adjustment of the immune system during early pregnancy, only a few studies have assessed immune cell changes during the late stage of pregnancy. A deeper understanding of these changes is necessary to elucidate the physiological mechanisms underlying the maintenance of pregnancy and the pathogenesis of PE and will lead to the identification of early biomarkers and effective therapeutic strategies to protect both the mothers and their babies.

PE is characterized by a systemic maternal inflammatory response, and the disturbed balance between immunotolerance and immunoactivation suggests the failure of immune regulation, allowing the exaggeration of inflammatory responses. Studies have shown that changes in the numbers and functions of immune cells associated with both adaptive and innate immunity contribute to the development of PE.[18],[19] Tim-3 is currently known as a versatile immunomodulator that affects several immune cell types and plays critical roles in both adaptive and innate immune regulation. We have previously reported that Tim-3 is significantly upregulated in decidual immune and stromal cells during the first trimester of pregnancy.[12],[13] Recently, Liao et al. also showed that the expression of Tim-3 at the maternal–fetal interface was reduced in a PE-like rat model.[20] In this study, we found that the number of Tim-3+ CD8+T cells decreased significantly in the peripheral blood, compared to that in the decidua, which suggests that Tim-3 was also associated with the tolerance phenotype at the maternal–fetal interface during the late stages of pregnancy. Consistently, in women with PE (during the third trimester), we found that the number of Tim-3-positive decidual CD8+T cells decreased markedly and that these cells were dysfunctional, compared to the case in healthy pregnant women during the third trimester.

Decidual CD8+T cells form the largest fraction of decidual T-cells and are the main candidates for recognizing and responding to human leukocyte antigen C expressed by trophoblasts. We found that Tim-3 expression in dCD8+T cells was defined as a CD8+T cell group that shows reduced cytotoxicity but is more active, as evidenced by low CD107a expression but strong proliferation and high expression of activation markers. A significant proportion of effector memory cells exhibited a Tim-3+ phenotype, and a similar pattern was observed in tumor-infiltrating T-cells.[21] TCMs have been reported to behave as helpers for Th1 and cytotoxic responses, and the majority of TEMs are prone to produce more anti-inflammatory cytokines under the influence of Tim-3 expression, thereby acquiring a regulatory phenotype at the maternal–fetal interface. Recently, Tim-3 was found to drive effector CD8+T cells in conjunction with CEACAM1.[22] In addition, our study showed that CEACAM1 increased the Tim-3 levels and altered Tim-3-induced cytokine production, indicating the important role of the CEACAM1/Tim-3 axis in CD8+T cells at the maternal–fetal interface. Intriguingly, anti-Tim-3 antibodies alone did not affect CD107 expression or cytokine production; this suggests that the dysfunction of CD8+T cells caused by abnormal Tim-3 expression occurred only upon stimulation with CEACAM1.

CEACAMs belong to the carcinoembryonic antigen (CEA) glycoprotein family. CEACAM1 is a multifunctional protein with a wide tissue distribution that regulates many cellular processes, including T-cell and NK cell regulation.[23],[24] CEACAM1 is expressed in decidual T-cells during early pregnancy, contributing to trophoblast invasion,[25],[26] which is beneficial for the maintenance of pregnancy. However, Pawel et al. showed elevated CEACAM1 levels in the serum of patients who were at a high risk of developing PE, especially in patients who developed PE.[27] Because most cases of PE occur during the third trimester, harvesting the decidual tissues of PE patients during the first trimester would not be helpful. We can only collect the decidual tissues of PE patients during cesarean section to reflect the state of immune cells. Further in vivo studies may help us investigate whether abnormal CEACAM1/Tim-3 signaling is an early causal event in the pathogenesis of PE.

In summary, we describe the decreased abundance and dysfunction of decidual Tim-3+CD8+T cells during the third trimester in PE pregnancies, which, theoretically, can result in a more likely condition for immune imbalance in PE. CEACAM1 affects cellular cytotoxicity and the production of pro-inflammatory and anti-inflammatory cytokines; this can be reversed by anti-Tim-3 antibodies. These findings suggest that altered CEACAM1/Tim-3 signaling may be an important factor contributing to the dysregulation of decidual CD8+T cells during the third trimester in PE pregnancies.

Acknowledgments

The authors thank all patients who donated clinical samples for this study.

Financial support and sponsorship

This work was supported by grants from the National Natural Science Foundation of China (31700799, 31970859, 81601311, and 81630036), the Shanghai Sailing Program (17YF1411600), the Training Program for Young Talents of the Shanghai Health System (2018YQ07), the Shanghai Chenguang Program (18CG09), and the Development Fund of Shanghai Talents (2018110).

Conflicts of interest

There are no conflicts of interest.



 
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